Compounds

ABSTRACT

This invention relates to compounds of formula I 
                         
their use as inhibitors of the microsomal prostaglandin E 2  synthase-1 (mPGES-1), to pharmaceutical compositions containing them, and their use as medicaments for the treatment and/or prevention of inflammatory diseases and associated conditions. A, M, W, R 1 , R 2 , R 3 , R 4 , R 6 , R 2 , R 7 , R 8 , R 9 , R a , R b  have meanings given in the description.

FIELD OF THE INVENTION

This invention relates to novel compounds, which are inhibitors of themicrosomal prostaglandin E₂ synthase-1 (mPGES-1), pharmaceuticalcompositions containing them, and their use as medicaments for thetreatment and/or prevention of inflammatory diseases and associatedconditions such as inflammatory/nociceptive pain.

BACKGROUND OF THE INVENTION

There are many acute and chronic diseases/disorders that areinflammatory in their nature including but not limited to rheumatoiddiseases e.g. rheumatoid arthritis, osteoarthritis, diseases of thevisceral system e.g. inflammatory bowel syndrome, autoimmune diseases,e.g. lupus erythematodes, lung diseases like asthma and COPD. Currenttreatment with non-steroidal anti-inflammatory drugs (NSAIDs) andcyclooxygenase (COX)-2 inhibitors are efficacious, but show a prevalencefor gastrointestinal and cardiovascular side effects. There is a highneed for new treatment options showing equivalent efficacy with animproved side effect profile.

mPGES inhibitors may show such an improved side effect profile becausethey block the generation of PGE₂ in a more specific manner as describedbelow.

NSAIDs and COX-2 inhibitors reduce inflammation and pain throughinhibition of one or both isoformes of COX enzymes. The cyclooxygenase(COX) enzyme exists in two forms, one that is constitutively expressedin many cells and tissues (COX-1), and one that in most cells andtissues is induced by pro-inflammatory stimuli, such as cytokines,during an inflammatory response (COX-2). COXs metabolise arachidonicacid to the unstable intermediate prostaglandin H₂ (PGH₂). PGH₂ isfurther metabolized to other prostaglandins including PGE₂, PGF_(2α),PGD₂, prostacyclin and thromboxane A₂. These arachidonic acidmetabolites are known to have pronounced physiological andpathophysiological activity including pro-inflammatory effects. PGE₂ inparticular is known to be a strong pro-inflammatory mediator, and isalso known to induce fever, inflammation and pain. Consequently,numerous drugs were developed with a view to inhibiting the formation ofPGE₂, including “NSAIDs” (non-steroidal antiinflammatory drugs) and“coxibs” (selective COX-2 inhibitors). These drugs act predominantly byinhibition of COX-1 and/or COX-2, thereby reducing the formation ofPGE₂. However, the inhibition of COXs has the disadvantage that itresults in the reduction of the formation of all metabolites downstreamof PGH₂, some of which are known to have beneficial properties. In viewof this, drugs which act by inhibition of COXs are thereforeknown/suspected to cause adverse biological effects.

For example, the non-selective inhibition of COXs by NSAIDs may giverise to gastrointestinal side-effects and affect platelet and renalfunction. Even the selective inhibition of COX-2 by coxibs, whilstreducing such gastrointestinal side-effects, is believed to give rise tocardiovascular problems.

An alternative treatment of inflammatory diseases that does not giverise to the above-mentioned side effects would thus be of real benefitin the clinic. In particular, a drug that preferably inhibits thetransformation of PGH₂ to the pro-inflammatory mediator PGE₂ selectivelymight be expected to reduce the inflammatory response in the absence ofa corresponding reduction of the formation of other, beneficialarachidonic acid metabolites. Such inhibition would accordingly beexpected to alleviate the undesirable side-effects mentioned above.

PGH₂ may be transformed to PGE₂ by prostaglandin E synthases (PGES). Twomicrosomal prostaglandin E synthases (mPGES-1 and mPGES-2), and onecytosolic prostaglandin E synthase (cPGES) have been described. mPGES-1is proposed to be closely linked to COX-2 and both enzyme's areupregulated during e.g. inflammation. Thus agents that are capable ofinhibiting the action of m PGES-1 and thereby reducing the formation ofPGE₂ are likely to be of benefit for the treatment of inflammation andmore general acute and chronic pain conditions

Benzimidazole and imidazopyridine derivatives with m PGES-1 inhibitoryactivity are disclosed in WO 2010/034796, WO 2010/034797, WO2010/034798, WO 2010/034799. WO2010/100249 describes a broad class ofdifferent 2-arylamino benzimidazoles in which the aryl group bears aparticular side chain.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula I,

in which

-   R¹ represents halo, —OH, —CN, C₁₋₃ alkyl, C₂₋₆ alkynyl, —OC₁₋₃ alkyl    which latter three groups are optionally substituted by one or more    substituents selected from fluoro, —CN, ═O, —OH, —OCH₃, —OCF₃;-   R², R³ and R⁴ independently represent hydrogen, halo, —CN, C₁₋₃    alkyl, —OC₁₋₃ alkyl which latter two alkyl groups are optionally    substituted by one or more substituents selected from fluoro, —CN,    ═O, —OH, —OCH₃, —OCF₃;-   R^(a) and R^(b) independently represent hydrogen, C₁₋₃ alkyl which    is optionally substituted by one or more fluorine atoms, or both    together with the carbon atom which they are bound to, form a C₃₋₇    cycloalkyl ring, or a 4-6 membered heterocycloalkyl ring which    latter two groups are optionally substituted by one or more fluorine    atoms;-   W represents —C(O)—, —S(O)—, —S(O)₂—, —C(O)O—, —C(O)NR^(d)— which    groups are bound to the nitrogen of the —NH— moiety via carbon or    sulfur atom;-   R^(d) represents hydrogen, C₁₋₃ alkyl;-   M represents C₁₋₈ alkyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl-C₀₋₄ alkyl-,    -   4-10 membered heterocycloalkyl-C₀₋₄ alkyl- which latter four        groups are optionally substituted by one or more groups selected        from        -   fluoro, —OH, ═O, —CN, —NH₂, C₁₋₃ alkyl, —NH(C₁₋₃ alkyl),            —N(C₁₋₃ alkyl)₂, azetidinyl, pyrrolidinyl, piperidinyl,        -   —OC₁₋₃ alkyl, [which latter seven alkyl groups can be            substituted by one or more substituents selected from            fluoro, —OH, —CN, —OC₁₋₂ alkyl (which latter alkyl group is            optionally substituted by one or more fluorine atoms)],        -   aryl, heteroaryl [which latter two groups are optionally            substituted by one or more substituents selected from halo,            —OH, —CN, C₁₋₃ alkyl, —OC₁₋₃ alkyl (which latter two alkyl            groups are optionally substituted by one or more fluorine            atoms)],        -   or    -   aryl, heteroaryl which latter two groups are optionally        substituted by one or more substituents selected from        -   halo, —OH, —CN, —NH₂, aryl, heteroaryl [which latter two            groups are optionally substituted by one or more            substituents selected from halo, —OH, —CN, C₁₋₃ alkyl,            —OC₁₋₃ alkyl (which latter two alkyl groups are optionally            substituted by one or more fluorine atoms)],        -   C₁₋₇ alkyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, 4-7 membered            heterocycloalkyl, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,            —OC₁₋₃ alkyl, —O—C₀₋₂alkyl-aryl, —SC₁₋₃ alkyl, (which latter            alkyl, alkynyl, heterocycloalkyl, aryl or cycloalkyl groups            are optionally substituted by one or more substituents            selected from fluoro, —CN, ═O, —NH₂, —NH(C₁₋₃ alkyl),            —N(C₁₋₃ alkyl)₂, —OH, —OC₁₋₃alkyl)];-   R⁶ represents hydrogen, C₁₋₅ alkyl, C₃₋₆ alkynyl, 4-7 membered    hetero-cycloalkyl-C₀₋₂alkyl or C₃₋₇cycloalkyl-C₀₋₂ alkyl (which    latter four groups are optionally substituted by one or more    substituents selected from fluoro, —CN, ═O, C₁₋₃ alkyl, —OH, —NH₂,    —OC₁₋₃ alkyl, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂);-   R⁷, R⁸ and R⁹ independently represent hydrogen, halo, —CN, C₁₋₅    alkyl, C₃₋₅ cycloalkyl-C₀₋₂ alkyl-, C₁₋₅ alkyl-O—, C₃₋₅    cycloalkyl-C₀₋₂ alkyl-O— (in which latter four groups the alkyl and    cycloalkyl fragments are optionally substituted by one or more    substituents selected from fluoro, —CN, —OH, —OC₁₋₃ alkyl or by one    or more C₁₋₃ alkyl groups which are optionally substituted by one or    more fluorine atoms);-   A represents —NHR¹⁰, —NR¹⁰R¹¹, or a    -   4-10-membered heterocycloalkyl group which is bound to the        benzimidazole through a nitrogen atom, and which is optionally        substituted by one or more substituents R¹²;-   R¹⁰ and R¹¹ independently represent C₁₋₇ alkyl, C₃₋₇ cycloalkyl-C₀₋₄    alkyl- or C₄₋₇ heterocycloalkyl-C₀₋₄ alkyl- [which latter three    groups are optionally substituted by one or more groups selected    from fluoro, —OH, NH₂, —CN, C₁₋₃ alkyl, —NH(C₁₋₃ alkyl), —N(C₁₋₃    alkyl)₂, —OC₁₋₅ alkyl, —OC₃₋₆ cycloalkyl, —OC₄₋₆ heterocycloalkyl    (which latter six groups are optionally substituted by one or more    substituents selected from fluoro, —CF₃, —CHF₂, —CH₂F, —CH₃)],    -   or    -   aryl-C₀₋₄ alkyl-, heteroaryl-C₀₋₄ alkyl- [which latter two        groups are optionally substituted by one or more substituents        selected from halo, —OH, —CN, C₁₋₃ alkyl, C₃₋₅ cycloalkyl, C₁₋₃        alkyl-O—,    -   C₃₋₅ cycloalkyl-O— (which latter four groups are optionally        substituted by one or more fluorine atoms)];-   each R¹² independently represents halo, —OH, —NH₂, ═O, —CN, C₁₋₄    alkyl, C₃₋₅ cycloalkyl-C₀₋₂ alkyl-, C₄₋₅ heterocycloalkyl-C₀₋₂    alkyl-, C₁₋₄ alkyl-O—, C₁₋₃ alkyl-C(═O)—, —C(═O)—NH(C₁₋₃ alkyl),    —C(═O)—N(C₁₋₃ alkyl)₂ [which latter six groups are optionally    substituted by one or more groups selected from fluoro, —OH, oxo,    —NH₂, —CN, C₁₋₃ alkyl, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —OC₁₋₃    alkyl, —OC₃₋₅ cycloalkyl [which latter five groups are optionally    substituted by one or more substituents selected from fluoro, —CF₃,    —CHF₂, —CH₂F],    -   or    -   aryl-C₀₋₄ alkyl-, heteroaryl-C₀₋₄ alkyl- [which latter two        groups are optionally substituted by one or more substituents        selected from halo, —OH, —CN, C₁₋₃ alkyl, C₃₋₅ cycloalkyl, C₁₋₃        alkyl-O—,    -   C₃₋₅ cycloalkyl-O— (which latter four groups are optionally        substituted by one or more fluorine atoms)];        or a salt thereof, particularly a physiologically acceptable        salt thereof.

In a second embodiment, in the general formula I, A, M, W, R², R³, R⁴,R⁶, R⁷, R⁸, R⁹, R^(a), R^(b) have the same meaning as defined in any ofthe preceding embodiments, and

-   R¹ represents halo, C₁₋₃ alkyl, —OC₁₋₃ alkyl which latter two groups    are optionally substituted by one or more fluorine atoms.

In another embodiment, in the general formula I, A, M, W, R¹, R³, R⁴,R⁶, R⁷, R⁸, R⁹, R^(a), R^(b) have the same meaning as defined in any ofthe preceding embodiments, and

-   R² represents hydrogen, halo, C₁₋₃ alkyl optionally substituted by    one or more fluorine atoms.

In another embodiment, in the general formula I, A, M, W, R¹, R², R⁶,R⁷, R⁸, R⁹, R^(a), R^(b) have the same meaning as defined in any of thepreceding embodiments, and

-   R³ and R⁴ independently represent hydrogen, halo.

In another embodiment, in the general formula I, A, M, W, R¹, R², R³,R⁴, R⁶, R⁷, R⁸, R⁹ have the same meaning as defined in any of thepreceding embodiments, and

-   R^(a), R^(b) independently represent hydrogen.

In another embodiment, in the general formula I, A, M, R¹, R², R³, R⁴,R⁶, R⁷, R⁸, R⁹, R^(a), R^(b) have the same meaning as defined in any ofthe preceding embodiments, and

-   W represents —C(O)—, —S(O)₂—, —C(O)O— which groups are bound to the    nitrogen of the —NH— moiety via carbon or sulfur atom.

In another embodiment, in the general formula I, A, W, R¹, R², R³, R⁴,R⁶, R⁷, R⁸, R⁹, R^(a), R^(b) have the same meaning as defined in any ofthe preceding embodiments, and

-   M represents C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl-C₀₋₁ alkyl-,    oxetanyl-, tetrahydrofuranyl-, azetidinyl-, pyrrolidinyl-,    piperidinyl- or one of the following heterocyclic groups

-   -   all of which groups are optionally substituted by one or more        groups selected from        -   fluoro, —OH, —CN, —NH₂, C₁₋₃ alkyl, —NH(C₁₋₂ alkyl), —N(C₁₋₂            alkyl)₂, —OC₁₋₂ alkyl [which latter four alkyl groups are            optionally substituted by one or more substituents selected            from fluoro],        -   phenyl, imidazolyl-[which latter two groups are optionally            substituted by one or more substituents selected from halo,            C₁₋₂ alkyl, OC₁₋₂alkyl (which latter two alkyl groups are            optionally substituted by one or more fluorine atoms)],        -   or    -   phenyl, naphthyl, furanyl, thienyl, oxazolyl, isoxazolyl,        thiazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, quinolynyl        which latter twelve groups are optionally substituted by one or        more substituents selected from        -   halo, aryl, heteroaryl [which latter two groups are            optionally substituted by one or more substituents selected            from halo, —CH₃, —CH₂F, —CHF₂, —CF₃],        -   C₁₋₂ alkyl, —OC₁₋₂ alkyl [which latter two groups are            optionally substituted by one or more fluorine atoms],        -   C₂₋₃ alkynyl, —O—C₀₋₂alkyl-phenyl [in which latter group the            phenyl is optionally substituted by one or more substituents            selected from halo, —CH₃, —CH₂F, —CHF₂, —CF₃].

In another embodiment, in the general formula I, A, M, W, R¹, R², R³,R⁴, R⁷, R⁸, R⁹, R^(a), R^(b) have the same meaning as defined in any ofthe preceding embodiments, and

-   R⁶ represents hydrogen, C₁₋₅ alkyl or C₃₋₇cycloalkyl-C₀₋₂alkyl    [which latter two groups are optionally substituted by one or more    substituents selected from fluoro, C₁₋₃ alkyl, —OC₁₋₃ alkyl,    —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂].

In another embodiment, in the general formula I, A, M, W, R¹, R², R³,R⁴, R⁶, R⁸, R^(a), R^(b) have the same meaning as defined in any of thepreceding embodiments, and

-   R⁷ and R⁹ independently represent hydrogen, halo, —CN, C₁₋₃ alkyl    optionally substituted by one or more fluorine atoms.

In another embodiment, in the general formula I, A, M, W, R¹, R², R³,R⁴, R⁶, R⁷, R⁹, R^(a), R^(b) have the same meaning as defined in any ofthe preceding embodiments, and

-   R⁸ represents hydrogen, halo, —CN, C₁₋₅ alkyl, C₃₋₅ cycloalkyl-C₀₋₂    alkyl- (in which latter two groups the alkyl and cycloalkyl    fragments are optionally substituted by one or more fluorine atoms,    or by one or more C₁₋₃ alkyl groups which are optionally substituted    by one or more fluorine atoms).

In another embodiment, in the general formula I, M, W, R¹, R², R³, R⁴,R⁶, R⁷, R⁸, R⁹, R^(a), R^(b) have the same meaning as defined in any ofthe preceding embodiments, and

-   A represents —NHR¹⁰, —NR¹⁰R¹¹, or    -   azetidinyl-, pyrrolidinyl-, piperidinyl-, morpholinyl-,        piperazinyl- or

-   -   all of which heterocyclic groups are optionally substituted by        one or more substituents R¹² and optionally annulated to a        phenyl or a 5- or 6-membered heteroaryl ring, while the above        mentioned groups are bonded to the benzimidazole core through a        nitrogen atom;

-   R¹⁰ and R¹¹ independently represent C₁₋₅ alkyl, C₃₋₆ cycloalkyl-C₀₋₁    alkyl-[which latter two groups are optionally substituted by one or    more groups selected from fluoro, —OH, C₁₋₃ alkyl],    -   or    -   aryl-C₀₋₁ alkyl- optionally substituted by one or more        substituents selected from halo, —OH, —CN, C₁₋₃ alkyl, C₁₋₃        alkyl-O—[which latter two groups are optionally substituted by        one or more fluorine atoms];

-   each R¹² independently represents halo, —OH, —CN, C₁₋₄ alkyl, C₁₋₂    alkyl-O—, C₁₋₂ alkyl-C(═O)—, —C(═O)—NH(C₁₋₂ alkyl), —C(═O)—N(C₁₋₂    alkyl)₂ [which latter five groups are optionally substituted by one    or more groups selected from fluoro, —OH, C₁₋₃ alkyl, —NH(C₁₋₂    alkyl), —N(C₁₋₂ alkyl)₂, —OC₁₋₂ alkyl (which latter four groups are    optionally substituted by one or more substituents selected from    fluoro, CF₃, CHF₂ or CH₂F)],    -   or    -   phenyl optionally substituted by one or more substituents        selected from halo or C₁₋₃ alkyl which is optionally substituted        by one or more fluorine atoms.

A further embodiment of the present invention comprises compounds offormula Ia

in which

-   R¹ represents halo, C₁₋₃ alkyl, —OC₁₋₃ alkyl which latter two groups    are optionally substituted by one or more fluorine atoms;-   R² represents hydrogen, halo, C₁₋₃ alkyl optionally substituted by    one or more fluorine atoms;-   R³ and R⁴ independently represent hydrogen, halo;-   W represents —C(O)—, —S(O)₂—, —C(O)O— which groups are bound to the    nitrogen of the —NH— moiety via carbon or sulfur atom;-   M represents C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl-C₀₋₁ alkyl-,    oxetanyl-, tetrahydrofuranyl-, azetidinyl-, pyrrolidinyl-,    piperidinyl- or one of the following heterocyclic groups

-   -   all of which groups are optionally substituted by one or more        groups selected from        -   fluoro, —OH, —CN, —NH₂, C₁₋₃ alkyl, —NH(C₁₋₂ alkyl), —N(C₁₋₂            alkyl)₂, —OC₁₋₂ alkyl, [which latter four alkyl groups are            optionally substituted by one or more fluorine atoms],            phenyl, imidazolyl-[which latter two groups are optionally            substituted by one or more substituents selected from halo,            C₁₋₂ alkyl, OC₁₋₂alkyl (which latter two alkyl groups are            optionally substituted by one or more fluorine atoms)],        -   or    -   phenyl, naphthyl, furanyl, thienyl, oxazolyl, isoxazolyl,        thiazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, quinolynyl        which latter twelve groups are optionally substituted by one or        more substituents selected from        -   halo, aryl, heteroaryl [which latter two groups are            optionally substituted by one or more substituents selected            from halo, —CH₃, —CH₂F, —CHF₂, —CF₃],        -   C₁₋₂ alkyl, —OC₁₋₂ alkyl [which latter two groups are            optionally substituted by one or more fluorine atoms],        -   C₂₋₃ alkynyl, —O—C₀₋₂alkyl-phenyl [in which latter group the            phenyl is optionally substituted by one or more substituents            selected from halo, —CH₃, —CH₂F, —CHF₂, —CF₃];

-   R⁶ represents hydrogen, C₁₋₅ alkyl or C₃₋₇cycloalkyl-C₀₋₂alkyl    [which latter two groups are optionally substituted by one or more    substituents selected from fluoro, C₁₋₃ alkyl, —OC₁₋₃ alkyl,    —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂];

-   R⁸ represents hydrogen, halo, —CN, C₁₋₅ alkyl, C₃₋₅    cycloalkyl-C₀₋₂alkyl- (in which latter two groups the alkyl and    cycloalkyl fragments are optionally substituted by one or more    fluorine atoms, or by one or more C₁₋₃ alkyl groups which are    optionally substituted by one or more fluorine atoms).

-   R⁹ represents hydrogen, halo, —CN, C₁₋₃ alkyl optionally substituted    by one or more substituents selected from fluorine atoms;

-   A represents —NHR¹⁰, —NR¹⁰R¹¹, or    -   azetidinyl-, pyrrolidinyl-, piperidinyl-, morpholinyl-,        piperazinyl- or

-   -   all of which heterocyclic groups can optionally be substituted        by one or more substituents R¹² and optionally annulated to a        phenyl or a 5- or 6-membered heteroaryl ring, whereby the above        mentioned groups are bonded to the benzimidazole core through a        nitrogen atom;

-   R¹⁰ and R¹¹ independently represent C₁₋₅ alkyl or C₃₋₆    cycloalkyl-C₀₋₁ alkyl-[which latter two groups are optionally    substituted by one or more groups selected from: fluoro, —OH, C₁₋₃    alkyl],    -   or    -   aryl-C₀₋₁ alkyl- which can be substituted by one or more        substituents selected from halo, —OH, —CN, C₁₋₃ alkyl, C₁₋₃        alkyl-O—[which latter two groups are optionally substituted by        one or more fluorine atoms];

-   each R¹² independently represents halo, —OH, —CN, C₁₋₄ alkyl,    -   C₁₋₂ alkyl-O—, C₁₋₂ alkyl-C(═O)—, —C(═O)—NH(C₁₋₂ alkyl),    -   —C(═O)—N(C₁₋₂ alkyl)₂ [which latter five groups are optionally        substituted by one or more groups selected from fluoro, —OH,    -   C₁₋₃ alkyl, —NH(C₁₋₂ alkyl), —N(C₁₋₂ alkyl)₂, —OC₁₋₂ alkyl,        (which latter four groups are optionally substituted by one or        more substituents selected from fluoro, CF₃, CHF₂ or CH₂F)],    -   or    -   phenyl optionally substituted by one or more substituents        selected from halo or C₁₋₃ alkyl which is optionally substituted        by one or more fluorine atoms.

In another embodiment, in the general formula I or Ia, A, M, W, R¹, R²,R³, R⁴, R⁶, R⁷, R⁹, R^(a), R^(b) have the same meaning as defined in anyof the preceding embodiments, and

-   R⁸ represents hydrogen, fluoro, chloro, CF₃, —CN.

In another embodiment, in the general formula I or Ia, M, W, R¹, R², R³,R⁴, R⁶, R⁷, R⁸, R⁹, R^(a), R^(b) have the same meaning as defined in anyof the preceding embodiments, and

-   A represents a group selected from

In another embodiment, in the general formula I or Ia, A, W, R¹, R², R³,R⁴, R⁶, R⁷, R⁸, R⁹, R^(a), R^(b) have the same meaning as defined in anyof the preceding embodiments, and

-   M represents a group selected from

A further embodiment of the present invention comprises compounds offormula Ia

in which

-   R¹ represents fluoro, chloro, CH₃, CHF₂, CH₂F, CF₃ or —OCF₃;-   R² represents hydrogen, fluoro or chloro;-   R³ and R⁴ independently represent hydrogen, fluoro;-   R⁶ represents hydrogen, —CH₃, —CH₂CF₃, cyclopropylmethyl-,    —CH₂CH₂—O—CH₃, —CH₂CH₂—N(CH₃)₂;-   R⁸ represents hydrogen, fluoro, chloro, CF₃, —CN;-   R⁹ represents hydrogen, fluoro;-   A represents a group selected from

-   W represents —C(O)—, —S(O)₂— which groups are bound to the nitrogen    of the —NH— moiety via carbon or sulfur atom;-   M represents a group selected from

TERMS AND DEFINITIONS USED

General Definitions:

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁₋₃-alkyl-” means an aryl group which is bound to aC₁₋₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail.

An asterisk is may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined, for example acyclopropylmethyl-group would be represented by the following drawing:

Tautomers/Stereochemistry/Solvates/Hydrates:

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers (e.g. 1H-benzimidazole may be considered to be identical to acorresponding compound containing a 3H-benzimidazole) and all stereo,optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Zisomers etc.) and racemates thereof as well as mixtures in differentproportions of the separate enantiomers, mixtures of diastereomers, ormixtures of any of the foregoing forms where such isomers andenantiomers exist, as well as salts, including pharmaceuticallyacceptable salts thereof and solvates thereof such as for instancehydrates including solvates of the free compounds or solvates of a saltof the compound.

Salts:

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. For example,such salts include salts from ammonia, L-arginine, betaine, benethamine,benzathine, calcium hydroxide, choline, deanol, diethanol-amine(2,2′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol,2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine,1H-imidazole, lysine, magnesium hydroxide,4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide,1-(2-hydroxy-ethyl)-pyrrolidine, sodium hydroxide, triethanolamine(2,2′,2″-nitrilotris(ethanol)), trometh-amine, zinc hydroxide, aceticacid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbicacid, L-aspartic acid, benzenesulfonic acid, benzoic acid,2,5-dihydroxybenzoic acid, 4-acet-amido-benzoic acid, (+)-camphoricacid, (+)-camphor-10-sulfonic acid, carbonic acid, cinna-mic acid,citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, ethylenediamonotetraacetic acid, formicacid, fumaric acid, galacaric acid, gentisic acid, D-glucoheptonic acid,D-gluconic acid, D-glucuronic acid, glutamic acid, glutantic acid,glutaric acid, 2-oxo-glutaric acid, glycero-phosphoric acid, glycine,glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid,hydrochloric acid isobutyric acid, DL-lactic acid, lactobionic acid,lauric acid, lysine, maleic acid, (−)-L-malic acid, malonic acid,DL-mandelic acid, methanesulfonic acid, galactaric acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid(embonic acid), phosphoric acid, propionic acid, (−)-L-pyroglutamicacid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearicacid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid,thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Furtherpharmaceutically acceptable salts can be formed with cations from metalslike aluminium, calcium, lithium, magnesium, potassium, sodium, zinc andthe like. (also see Pharmaceutical salts, Berge, S. M. et al., J. Pharm.Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts) also comprise a part of the invention.

Halogen:

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

Alkyl:

The term “C_(1-n)-alkyl”, wherein n is an integer from 2 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

Alkynyl:

The term “C_(2-n)-alkynyl”, wherein n is an integer from 3 to n, is usedfor a group as defined in the definition for “C_(1-n)-alkyl” with atleast two carbon atoms, if at least two of those carbon atoms of saidgroup are bonded to each other by a triple bond.

Cycloalkyl:

The term “C_(3-n)-cycloalkyl”, wherein n is an integer >3, either aloneor in combination with another radical denotes a mono-, bi-, tri- ortetracyclic, saturated, hydrocarbon radical with 3 to n C atoms. Forexample the term C₃₋₇-cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

The term “cycloalkyl” encompasses fused, bridged and spirocyclicsystems. The cycloalkyl radical may further be fused to a phenyl ring orto a 5-6-membered heteroaryl ring, e.g. a thienyl-, pyrrolyl-,thiazolyl-, oxazolyl-, isoxazolyl-, imidazolyl-, pyrazolyl-, triazolyl-,tetrazolyl-, pyridinyl-, pyrimidinyl- pyrazinyl- or pyridazinyl-ring.

Furthermore, the term “cycloalkyl” includes the following exemplarystructures, which are not depicted as radicals as they may be attachedthrough a covalent bond to any atom of the cycloalkyl ring fragment butnot to an atom of the aryl or heteroaryl fragment:

Heterocycloalkyl:

The term “4-n-membered heterocycloalkyl”, wherein n is an integer >4,means a saturated or partially unsaturated mono- or polycyclic ringsystem containing one or more heteroatoms selected from N, O orS(O)_(r), wherein r=0, 1 or 2, consisting of 4 to n ring atoms. Theheterocycloalkyl ring system may further be fused to a phenyl- or5-6-membered heteroaryl ring such as a thienyl-, pyrrolyl-, thiazolyl-,oxazolyl-, isoxazolyl-, imidazolyl-, pyrazolyl-, triazolyl-,tetrazolyl-, pyridinyl-, pyrimidinyl- pyrazinyl- or pyridazinyl-ring.The term “heterocycloalkyl” is intended to include all the possibleisomeric forms. The term “heterocycloalkyl” includes the followingexemplary structures, which are not depicted as radicals as they may beattached through a covalent bond to any atom of the heterocycloalkyl orcycloalkyl ring fragment but not to an atom of the aryl or heteroarylfragment:

Aryl:

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may further be fused to a second 5- or6-membered aromatic, saturated or unsaturated carbocyclic group. Theterm “aryl” includes phenyl, indanyl, indenyl, naphthyl, anthracenyl,phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl which may beattached through a covalent bond to any atom of the aromatic fragment.

Heteroaryl:

The term “heteroaryl” means a mono- or polycyclic ring system containingone or more heteroatoms selected from N, O or S(O)_(r), wherein r=0, 1or 2, consisting of 5 to 14 ring atoms wherein at least one of theheteroatoms is part of the aromatic ring which may further be fused to asecond 5- or 7-membered aromatic, saturated or unsaturated cycloalkyl orheterocycloalkyl group. The term “heteroaryl” is intended to include allthe possible isomeric forms.

The term “heteroaryl” includes the following exemplary structures, whichare not depicted as radicals as they may be attached through a covalentbond to any atom of the mono or bicyclic heteroaryl ring but not to anatom of the cycloalkyl or heterocycloalkyl fragment:

Methods of Preparation

Compounds of the present invention can be prepared in accordance withtechniques that are well known to those skilled in the art, for exampleas described hereinafter and in the experimental section or in analogyto methods described in WO2010/034796 and WO2010/100249. According to afurther aspect of the invention there is provided a process for thepreparation of a compound of formula I, which process can be performedfor example according to the following schemes A-B.

The reaction between phenylenediamine X and the thioisocyanate XI (Stepa) can be performed under standard conditions known to those skilled inthe art—for example in analogy to the process described in WO2010/034796and WO2010/100249—in presence of a suitable solvent such as diethylether (Et₂O), dimethylformamide (DMF), dichloromethane (DCM),acetonitrile (MeCN) and/or tetrahydrofuran (THF). The reaction ispreferably performed in the presence of a suitable reagent whichenhances the cyclisation step as for instance CH₃—I or a carbodiimidebased compound such as N,N′-dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI, or its salt, e.g.hydrochloride) or N,N′-diisopropylcarbodiimide (DIC) or in presence ofan amine base e.g. triethylamine (TEA) or diisopropyl ethyl amine(DIPEA). The reaction may proceed at any suitable temperature between 0°C. to 200° C., preferably between room temperature and 100° C. Step acan be performed in a step-wise reaction including isolation of thethiourea intermediates XIIa and/or XIIb or in a one-pot procedure.

Alternatively, the compounds of formula I can be synthesized accordingto scheme B.

The protecting group PG^(amino) in XV is a literature known protectinggroup of an amino group well known to those skilled in the art as forexample described in “Protective Groups in Organic Synthesis”, 3^(rd)edition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1999), forexample a tert-butoxycarbonyl-, benzyloxycarbonyl-, ethoxycarbonyl-,methoxycarbonyl-, allyloxycarbonyl- or trifluormethylcarbonyl group.

Step a) can be performed as described in Scheme 1.

Step d) PG^(amino) in XVI can be removed in accordance with techniquesthat are well known to those skilled in the art and which areexemplified hereinafter. For example XVI can be deprotected using anappropriate agent (depending on the protecting group) such as forexample trifluoro acetic acid, HCl or H₂SO₄ solutions, KOH; Ba(OH)₂, Pdon carbon (Pd/C), trimethylsilyl iodide or other conditions as describedin “Protective Groups in Organic Synthesis”, 3^(rd) edition, T. W.Greene & P. G. M. Wutz, Wiley-Interscience (1999). Appropriateco-solvent for this step is for example DCM, THF, MeCN, DMF, DMA, NMP ormixtures of the above mentioned solvents at any suitable temperaturebetween 0° C. to 100° C.

The amide formation in step e) can be performed with the acids HO—W-Mand an additional in-situ activating agent like 1-propylphosphonic acidcyclic anhydride (PPA), O-(benzo

triazol-1-yl)-N,N,N′,N′-tetra-methyl-uronium tetrafluoroborate (TBTU),O-(benzo

triazol-1-yl)-N,N,N′,N′-tetramethyl-uro-nium hexafluorophosphate (HBTU),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate(HATU), DCC, EDCI, carbonyl

di

imidazole (CDI), carbonylditriazole (CDT),1-chloro-2-methyl-propenyl-dimethylamine, oxalyl chloride or otheractivating agents of the state of the art. Alternatively, the amideformation can be performed directly with the corresponding acid chlorideCl-W-M under analogous conditions without an additional in situactivating agent. The coupling reaction is preferably performed in thepresence of a base such as NaOH, KOH, NaHCO₃, TEA, DIPEA, pyridine,N,N-dimethylaminopyridine (DMAP) or other appropriate bases of the stateof the art and for example described in Houben-Weyl, “Methods in OrganicSynthesis”, Vol. E22a, p 425ff. The coupling reactions are performed inan appropriate solvent for example DCM, dioxane, THF, MeCN, DMF,dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or in mixtures of theabove mentioned solvents at any suitable temperature between 0° C. to100° C.

The synthesis of the building blocks X can be performed in a proceduredescribed in scheme C—wherein all variable groups in XIII and XIV are asdefined in claim 1 and LG is a leaving group on the aromatic ring (forexample a fluoro, chloro, bromo, iodo or trifluormethylsulfonylgroup)—using standard reaction conditions known to those skilled in theart which are exemplified in the experimental part in detail.

Step b can be performed by an aromatic substitution reaction of thebuilding block XIII with the amine A-H or an appropriate salt thereofand using literature known reaction conditions. For example the reactioncan be performed employing a building block XIII wherein LG ispreferably a fluoro or chloro substituent in presence of a suitable baselike K₂CO₃, Na₂CO₃, Cs₂CO₃, TEA, DIPEA in an appropriate solvent forexample DMF, DMSO, DMA, NMP or mixtures of the above mentioned solventsat any suitable temperature between 0° C. to 180° C. Alternatively thereaction can also be performed in presence of a Pd-catalyst, in thiscase the preferred groups LG are bromo, iodo or trifluormethylsulfonyl.For example Pd(PPh₃)₄ can be used in presence of a suitable base forexample K₂CO₃, Na₂CO₃, Cs₂CO₃, TEA, DIPEA in an appropriate solvent forexample THF, MeCN, DMF or mixtures of the mentioned solvents preferablyat a temperature between 0° C. to 120° C.

The nitro group in precursor XIV can be reduced to the amino group instep c) under literature known reduction conditions for example viahydrogenation (preferably at 1-5 bar) in presence of Pt/C, Pd/C orRaney-Nickel (Ra/Ni) in MeOH, EtOH or THF or mixtures thereof,optionally under acidic conditions in presence of HCl, or by usingSnCl₂/HCl, Na₂S₂O₄, Zn/HCl, Fe/HCl, Fe-powder/aqueous NH₄Cl solution oraccording to procedures described in the literature for example R.Larock, Comprehensive Organic Transformations, VCH Verlagsgemeinschaft,Weinheim (1989). Appropriate solvent for this step is for example DCM,THF, MeCN, DMF, DMA, NMP, EtOH, MeOH or mixtures of the above mentionedsolvents at any suitable temperature between 0° C. to 100° C.

The synthesis of the building blocks XI and XV—wherein all variablegroups are as defined in claim 1 and PG^(amino) is a protecting group ofthe benzylic amino group—is employing standard reaction conditionsaccording to scheme D known to those skilled in the art which areexemplified in the experimental part in detail or in WO2010/100249.

Step f) can be performed according to standard literature procedures forexample with reagents such as 1,1′-thiocarbonyldi-2-pyridone,O,O′-di-2-pyridylthiocarbonate, 1,1′-thiocarbonyldiimidazole or withthiophosgene in a solvent as for example DCM, dioxane or DMF attemperatures between 0-150° C. and optionally under addition of a baselike DMAP or TEA.

The building blocks XVII and XVIII can be prepared according to schemeE:

The amide formation in step g) can be performed in analogy to step c) orstep e) to synthesize compound XVII or by using common reagents foramino group protection for example di-tert-butyl-dicarbonate, methyl-,ethyl-, benzyl or allyl-chloroformate under standard reaction conditionsas described in “Protective Groups in Organic Synthesis”, 3^(rd)edition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1999) tosynthesize compounds XVIII.

The nitro group in precursor XVIIa or XVIIIa can be reduced to the aminogroup in step h) under literature known reduction conditions for examplevia hydrogenation (preferably at 1-5 bar) in presence of Pd/C, Pt/C orRaNi in MeOH, EtOH or THF optionally under acidic conditions in presenceof HCl, or by using SnCl₂/HCl, Na₂S₂O₄, Zn/HCl, Fe/HCl,Fe-powder/aqueous NH₄Cl solution or according to procedures described inthe literature for example R. Larock, Comprehensive OrganicTransformations, VCH Verlagsgemeinschaft, Weinheim (1989). Appropriatesolvent for this step is for example DCM, THF, MeCN, DMF, DMA, NMP,EtOH, MeOH or mixtures of the above mentioned solvents at any suitabletemperature between 0° C. to 100° C.

The building blocks XIX and XX can be prepared according to scheme F-H:

Step i) can be performed via hydrogenation (1-5 bar) with a catalystlike Pd/C, PtO₂ or RaNi in a suitable solvent like MeOH or EtOHoptionally using HCl or NH₃ as additive at temperatures between 0-60° C.or via reduction with LiAlH₄ or BH₃-containing reagents in a suitablesolvent like THF, MeOH or EtOH under literature-known conditions.

Step j) can be performed under the amide coupling conditions describedfor step e) and using NH₃ as coupling partner, for example1-chloro-2-methyl-propenyl-dimethylamine in THF can be used asactivating agent.

Step k) can be performed using LiAlH₄ or BH₃-containing reagents underliterature known conditions as for example compiled in R. C. Larock,Comprehensive Organic Transformations, VCH, 1989, p. 432-433, preferablywith LiAlH₄ in THF at 0-80° C.

Alternatively compounds XIX and XX can be prepared as described inWO2010/100249 or according to scheme G

Step k) can be performed mixing XXIV with reagent XXV in concentratedH₂SO₄ or F₃C—SO₃H at temperatures between 0-150° C., preferably between20-80° C.

Step l) can be performed using literature known deprotection proceduresfor the corresponding nitrogen protecting groups for example treatmentof the phthalimide with hydrazine or cleavage of the amide bond usingbases like NaOH in MeOH or EtOH at temperatures between 20-80° C. orunder acidic conditions using aqueous HCl solution or HCl in dioxane attemperatures between 20-80° C.

Alternatively compounds XIX and XX can be prepared according to scheme H

Step m) can be performed mixing XXX with HO—NH₂ in an appropriatesolvent for example MeCN, DCM, THF, optionally using HCl as additive attemperatures between 0-60° C.

Step n) can be performed applying literature known reduction conditionsfor example via hydrogenation preferably at 1-5 bar H₂ pressure inpresence of Pd/C or Ra—Ni in MeOH, EtOH or THF optionally using HCl orHOAc as catalyst, or by using SnCl₂/HCl, Zn/HCl, Fe/HCl,Fe-powder/aqueous NH₄Cl solution or according to procedures described inthe literature for example R. Larock, Comprehensive OrganicTransformations, VCH Verlagsgemeinschaft, Weinheim (1989).

Step o) can be performed applying literature known reduction conditionse.g. using ammonia or ammonium salts (e.g. ammonium acetate) and Boranereagents, for example NaBH₃CN, BH₃-THF-complex or BH₃—SMe₂-complex inwater, MeOH, EtOH, THF or mixtures thereof, under buffered conditionspreferably at a pH between 5-9 or employing hydrogenations using Pd/C orRa—Ni as catalysts in MeOH, EtOH or THF optionally using HCl or HOAc asco-catalyst or according to procedures described in the literature forexample in WO2010/100249 or R. Larock, Comprehensive OrganicTransformations, VCH Verlagsgemeinschaft, Weinheim (1989).

Biological Assays

The aim of this assay is to determine the affinity of a test compoundfor the mPGES-1 enzyme.

Similar assays to measure inhibition of mPGES-1 have previously beendescribed in the literature [1, 2].

LITERATURE REFERENCES

-   1. Riendeau, D., R. Aspiotis, D. Ethier, Y. Gareau, E. Grimm, J.    Guay, S. Guiral, H. Juteau, J. Mancini, N. Methot, J. Rubin, and R.    Friesen, Inhibitors of the inducible microsomal prostaglandin E2    synthase (mPGES-1) derived from MK-886. Bioorg Med Chem Lett, 2005.    15(14): p. 3352-3355.-   2. Cote, B., L. Boulet, C. Brideau, D. Claveau, D. Ethier, R.    Frenette, M. Gagnon, A. Giroux, J. Guay, S. Guiral, J. Mancini, E.    Martins, F. Masse, N. Methot, D. Riendeau, J. Rubin, D. Xu, H.    Yu, Y. Ducharme, and R. Friesen, Substituted phenanthrene imidazoles    as potent, selective, and orally active mPGES-1 inhibitors. Bioorg    Med Chem Lett, 2007. 17(24): p. 6816-6820.    Assay A: mPGES-1 Enzyme Assay    List of Reagents Used:    -   Glutathione (Sigma, G-4251)    -   Freeze culture in Rosetta E coli expression strain.    -   LB growth media with Ampillicillin (Amp) final concentration in        culture 50 μg/mL    -   Chloroamphenicol stock 34 mg/mL (chloro) final concentration in        culture 34 μg/mL    -   Sterile growth flasks for 500 mL-1 liter cultures    -   0.1 M KP, buffer pH 7.4    -   9.25% HCl    -   PGH₂ (0.25 mM)    -   Fe (II) Cl₂ tetrahydrate, 99% (Sigma, 220229)    -   384-well plate with compounds    -   96-well plate, polypropylene (Thermo fast 96 skirted VWR)    -   384-well plate polypropylene PCR plate (Greiner 785201)    -   Greiner 384-well plate pp (In vitro cat. no. 781280)    -   Adhesive sealing film for 96-well plates (Sigma-Aldrich)    -   Aluminium foil (PCR foil, 310-0030-127-471 from Labora)    -   PBS (GIBCO 14040)    -   Prostaglandin E₂ Assay (Cisbio, cat. no. 62P2APEC)    -   Biomek FX robot (Beckman Coulter)    -   Biomek NX robot (Beckman Coulter)    -   Multidrop; micro or combi (ThermoLabsystems)    -   Plate reader: Safire2 (Tecan)

Microsomes from Rosetta E. coli bacteria expressing recombinant humanmPGES-1 can be derived as described below:

Inoculate 5 mL LB with Amp and Chloro with bacteria from freeze culture.Incubate overnight at 37° C. with 200 rpm. Thereafter, inoculate 500-800mL LB containing Amp and Chloro with the 5 mL on culture and grow toOD640 of 0.6-0.8. Chill the culture to +4° C. before induction. Inducethe culture with IPTG at a final concentration of 400 μM. Express theprotein at room temp 18-23° C. with 200 rpm shaking overnight.

The following steps can be performed on the following day:

-   -   1. Spin down the cells in 250 mL centrifuge flasks for 15 min at        7000 rpm    -   2. Dissolve the pellet from 250 mL culture in 12.5 mL        homogenization buffer    -   3. Disintegrate the cells by sonication, 4×10 seconds at 35%        amplitude    -   4. Add 2.5 mL MgCl₂ (100 mM) and DNase 12.5 μL (0.8 mg/mL) and        incubate on ice for 30 min    -   5. Spin down the bacteria debris and save the supernatant, 7000        rpm for 15 min    -   6. Isolate the protein containing membranes in the supernatant        by ultracentrifugation 45000×g for 1 hour.    -   7. Discard the supernatant and dissolve the pellet in 20 mM KPi        buffer and aliquot the enzyme and store aliquots at −80° C.

Before each experiment is performed an aliquot of the enzyme is thawedand it can then be dissolved in 0.1 M KP, pH 7.4 buffer containing 2.5mM GSH. 50 μL of this enzyme solution is subsequently dispensed in a384-well plate at room temperature. 0.5 μL of the inhibitor dissolved inDMSO is thereafter added to each well and incubated for 25 minutes atroom temperature. Subsequently, 2 μL of PGH₂ dissolved in an appropriatesolvent is added to each well and after one minute at room temperature,the acidified stop solution containing FeCl₂ is added. 4 μL of the totalvolume is transferred to a separate plate and diluted 750-fold in twoseparate steps before quantification of PGE₂.

In order to quantitate the amount of PGE₂ that has been formed, ahomogenous time resolved fluorescent (HTRF) detection of PGE₂ can beperformed by the use of a commercially available kit from CisBioessentially according to the manufacturer's protocol. Briefly, 10 μL ofthe diluted sample is transferred to a white 384-well plate and thefollowing steps can be performed in a sequential manner at roomtemperature or as indicated.

-   -   5 μL reconstitution buffer as supplied by the manufacturer is        added to the negative control (NC) wells.    -   The plate is covered with adhesive sealing film.    -   The plate can now be centrifuged at 1200 rpm for 1 minute.    -   The NC samples are covered with sealing film.    -   250 μL d2 labeled PGE₂ (d2-PGE₂) can be diluted in 4750 μL        reconstitution buffer as supplied by the manufacturer    -   250 μL Eu3+-cryptate can be diluted in 4750 μL reconstitution        buffer as supplied by the manufacturer    -   5 μL d2-PGE₂ can now be added to rows 1 to 24, by using a        multidrop. The sealing film is thereafter removed from the NC        wells.    -   5 μL Eu3+-cryptate labeled anti-PGE₂ can now be added to rows 1        to 24 by using a Multidrop.    -   The plate can now be covered with sealing film.    -   The plate can now be centrifuge at 1200 rpm for 1 minute and        place at 4° C. overnight.

After the overnight incubation the fluorescence is measured by the useof an appropriate microplate reader. The fluorescence of Eu3+-cryptateand d2-PGE₂ are measured using the following excitation and emissionwavelength, europium cryptate: λ_(max) ^(ex)=307 nm, λ_(max) ^(em)=620nm and d2: λ_(max) ^(ex)=620 nm, λ_(max) ^(em)=665 nm), respectively.The extent of the specific HTRF is measured as a ratio of the emissionintensity at 665 nm vs. that at 620 nm. A standard curve using syntheticPGE₂ is used to quantify the amount of PGE₂ in unknown samples. Thedegree of inhibition can be calculated as percent inhibition by dividingthe amount of PGE₂ formed in unknown samples by the amount of PGE₂formed in control samples.

Assay B: mPGES-1 Enzyme Assay (Modified)

mPGES Protein Production

Microsomes from Rosetta E. coli bacteria expressing recombinant humanmPGES-1 can be derived as described below:

Inoculate 5 ml LB with Ampicilin (50 μg/ml) and Chloramphenicol (34μg/ml) with bacteria from freeze culture. Incubate 8 h at 37° C. with200 rpm. Thereafter, inoculate 500-1000 ml LB containing Ampicilin andChloramphenicol with the 5 ml on culture and grow to OD640 of 0.8-1.0.Chill the culture to +4° C. before induction. Induce the culture withIPTG at a final concentration of 400 μM. Express the protein at roomtemp 18-23° C. with 200 rpm shaking overnight.

The following steps can be performed on the following day:

-   -   1. Spin down the cells in 250 ml centrifuge flasks for 15 min at        7000 rpm (Beckmann Coulte Avanti J-E centrifuge)    -   2. Dissolve the pellet from 250 ml culture in 12.5 ml        homogenization buffer    -   3. (15 mM Tris-HCL pH8, 1 mM EDTA pH8, 0.25 mM Sucrose, 2.5 mM        GSH, 1 Tablet Protease inhibitor per 50 ml buffer)    -   4. Disintegrate the cells by sonication, 5×10 seconds at 48%        amplitude of a 750 W sonifier    -   5. Add 2.5 ml MgCl₂ (100 mM) and DNase 12.5 μl (0.8 mg/ml) and        incubate on ice for 30 min    -   6. Spin down the bacteria debris and save the supernatant, 7000        rpm for 15 min    -   7. Isolate the protein containing membranes in the supernatant        by ultracentrifugation 120000×g for 2 hour at 4° C. (Sorvall        T880 rotor).    -   8. Discard the supernatant and dissolve the pellet in 20 mM        Potassium phosphate buffer pH7.4 (KH₂PO₄ and K₂HPO₄) buffer by        sonication (5×10 s, 30% of a 50 W sonifier) and aliquot the        enzyme and store aliquots at −80° C.

Before each experiment is performed an aliquot of the enzyme is thawedand it can then be dissolved in 0.1 M Potassium phosphate buffer pH7.4(KH₂PO₄ and K₂HPO₄) buffer containing 2.5 mM GSH.

mPGES-1 Enzyme Assay

The aim of this assay is to determine the affinity of a test compoundfor the mPGES-1 enzyme.

47 μl of recombinant human mPGES-1 (˜0.5 μg protein/well) containingmicrosomal suspension in a buffer containing GSH, (2.5 mmol/LL-Glutathione reduced, dissolved in 0.1 mol/L Phosphat Buffer pH 7.4) isdispensed in a 384-well plate and thereafter 1 μl of the testcompound(s) is/are added and incubated for 25 minutes at roomtemperature. The enzyme reaction is started by the addition of 2 ul PGH2(final conc. 2 μM) dissolved in water-free Diglyme. After 60 seconds thereaction is terminated by addition of a stop solution containing FeCl₂(10 μL 0.074 mol/l FeCl₂). The samples are diluted between 1:25 in PBS(Phosphate Buffered Saline). 10 μl of the diluted samples aretransferred to 384-well low volume plate. In order to quantify theamount of PGE₂ that has been formed, a homogenous time resolvedfluorescent (HTRF) detecting of PGE₂ has been performed using acommercially available kit from Cisbio according to the manufacturesrecommendation. This HTRF-based assay has been described in detail (see:Goedken et al., J Biomol Screen, 2008, 13(7), 619-625). Briefly, thediluted samples are mixed with 5 μl PGE₂-d2 conjungate and 5 μlanti-PGE₂ cryptate conjungate. After an incubation period of the platesovernight, the fluorescence is measured by the use of an appropriatemicroplate reader.

The fluorescence of Europium cryptate (maxex=307 nm, maxem=620 nm) andd2-PGE₂ (maxex=620 nm, maxem=665 nm) are measured.

The extent of the specific HTRF is measured as a ratio of the emissionintensity at 665 nm vs. that at 620 nm at an excitation puls of 320 nm.The quantification plate contains also wells with differentconcentrations of PGE₂ as calibration curve for the calculation of thePGE₂ concentrations from the HTRF ratio values.

From all mPGES enzyme assay the background is subtracted and the IC₅₀ iscalculated over a nonlinear regression with conventional software.

TABLE 1-A mPGES-1 inhibitory effect (IC₅₀ values in nM) of compounds ofthe invention in the biological assays A IC50 IC50 IC50 IC50 example[nM] example [nM] example [nM] example [nM] 1 2.5 11 140 28 24 72 11 219 13 2.6 29 105 73 61 3 715 14 4.8 30 300 74 144 4 24 15 3 34 100 758.7 5 3.8 16 15 54 6.6 76 3.1 6 215 17 24 65 15 77 10 7 74 18 79 66 1078 1.7 8 106 19 52 68 4 79 2.4 9 143 20 >100 69 9 80 54 10 31 21 30 712.5 81 6.7 82 1.7 83 1.3 84 7.3 85 20 86 7.1 87 14 88 5.3 89 6.1 90 2.291 3.6 93 17 94 3.5 95 2.1 96 4.1 99 4.0 100 7.7 101 2.8 102 2.4 103 2.0104 2.4 105 3.9 106 5.7 107 13 108 5.8 109 5.2 110 1.5 111 19 112 22 11311 114 4.8 115 9.2 116 5.9 117 120 118 53 119 >100 120 266 121 60 1227.9 123 29 124 2.6 125 32 126 6.7 127 26 128 172 129 634 130 15 132 124133 25

TABLE 1-B mPGES-1 inhibitory effect (IC₅₀ values in nM) of compounds ofthe invention in the biological assays B IC50 IC50 IC50 IC50 example[nM] example [nM] example [nM] example [nM] 12 174 33 3 37 7.8 40 5.7 489 51 23 52 2.2 53 3.5 59 2 61 5 70 6.5 92 39 97 3.1 98 6.5 131 5Method of Treatment

The present invention relates to compounds of formula I which are usefulin the prevention and/or treatment of a disease and/or condition inwhich the inhibition of prostaglandin E synthases, in particular that ofthe microsomal prostaglandin E₂ synthase-1 (mPGES-1) is of therapeuticbenefit, including but not limited to the treatment and/or prevention ofinflammatory diseases and/or associated conditions.

The term “inflammation” will be understood to include any inflammatorydisease, disorder or condition per se, any condition that has aninflammatory component associated with it, and/or any conditioncharacterised by inflammation as a symptom, including inter alia acute,chronic, ulcerative, specific, allergic and necrotic inflammation, andother forms of inflammation known to those skilled in the art. The termthus also includes, for the purposes of this invention, inflammatorypain, pain generally and/or fever.

Where a condition has an inflammatory component associated with it, or acondition characterised by inflammation as a symptom, the skilled personwill appreciate that compounds of the invention may be useful in thetreatment of the inflammatory symptoms and/or the inflammationassociated with the condition.

Compounds of the invention may also have effects that are not linked toinflammatory mechanisms, such as in the reduction of bone loss in asubject. Such conditions include osteoporosis, osteoarthritis, Paget'sdisease and/or periodontal diseases.

A further aspect of the present invention relates to a compound offormula I as a medicament. Another aspect of the present invention isthe use of compounds of formula I for the treatment and/or prevention ofa disease and/or condition in which the inhibition of the mPGES-1 is oftherapeutic benefit.

A further aspect of the present invention is the use of a compound offormula I for the treatment and/or prevention of inflammatory diseasesand/or associated conditions.

The present invention also relates to the use of compounds of formula Ifor the treatment and/or prevention of the following diseases andconditions:

1. Rheumatic diseases or autoimmune diseases or muscoskeletal diseases:all forms of rheumatic diseases including e.g. soft tissue rheumatism,rheumatoid arthritis, polymyalgia rheumatica, reactive arthritis,tenosynovitis, gout or metabolic arthritis, bursitis, tendonitis,juvenile arthritis, spondyloarthropathies like e.g. spondylitis,ankylosing spondylitis, psoriatric arthropathy; sarcoidosis,fibromyalgia, myositis, polymyositis, osteoarthritis, traumaticarthritis, collagenoses of any origin e.g. systemic lupus erythematosus,scleroderma, dermatomyositis, Still's Disease, Sjögren syndrome, Feltysyndrome; rheumatic fever and rheumatic heart disease, diseases of bloodvessels like vasculitis, polyarthritis nodosa, Behcet's syndrome, giantcell arthritis, Wegener's granulomatosis, Henoch-Schönlein purpura;psoriatic arthritis, fungal arthritis, in particular including painassociated with any of the aforementioned conditions;2. Headaches such as migraines with and without aura, tension-typeheadaches, cluster headaches and headaches with different origins;3. Sympathetically maintained pain like complex regional pain syndromeType I and II;4. Neuropathic pain such as low back pain, hip pain, leg pain,non-herpetic neuralgia, post herpetic neuralgia, diabetic neuropathy,nerve injury-induced pain, acquired immune deficiency syndrome (AIDS)related neuropathic pain, head trauma, toxin and chemotherapy causednerve injuries, phantom limb pain, multiple sclerosis, root avulsions,painful traumatic mononeuropathy, painful polyneuropathy, thalamic painsyndrome, post-stroke pain, central nervous system injury, post surgicalpain, carpal tunnel syndrome, trigeminal neuralgia, post mastectomysyndrome, postthoracotomy syndrome, stump pain, repetitive motion pain,neuropathic pain associated hyperalgesia and allodynia, alcoholism andother drug-induced pain;5. Cancer pain induced by or associated with tumors such as bone tumors,lymphatic leukemia; Hodgkin's disease, malignant lymphoma;lymphogranulomatoses; lymphosarcoma; solid malignant tumors; extensivemetastases;6. Visceral disorders such as chronic pelvic pain, pancreatitis, pepticulcer, interstitial cystitis, cystitis, renal colic, angina,dysmenorrhoea, menstruation, gynaecological pain, irritable boweldisease (IBS), inflammatory bowel disease, Crohn's disease andulcerative colitis, nephritis, prostatitis, vulvodynia, non-ulcerdyspepsia, non-cardiac chest pain, myocardial ischemia;7. Inflammation associated diseases of ear, nose, mouth and throat likeinfluenza and viral/bacterial infections such as the common cold,allergic rhinitis (seasonal and perennial), pharyngitis, tonsillitis,gingivitis, larhyngitis, sinusitis, and vasomotor rhinitis, fever, hayfever, thyroiditis, otitis, dental conditions like toothache,perioperative and post-operative conditions, trigeminal neuralgia,uveitis; iritis, allergic keratitis, conjunctivitis, blepharitis,neuritis nervi optici, choroiditis, glaucoma and sympathetic opthalmia,as well as pain thereof;8. Neurological diseases such as cerebral oedema and angioedema,cerebral dementia like e.g. Parkinson's and Alzheimers disease, seniledementia; multiple sclerosis, epilepsy, drug resistant epilepsy, stroke,myasthenia gravis, brain and meningeal infections likeencephalomyelitis, meningitis, including HIV as well as schizophrenia,delusional disorders, autism, affective disorders and tic disorders;9. Work-related diseases like pneumoconiosis, including aluminosis,anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis,tabacosis and byssinosis;10. Lung diseases such as asthma including allergic asthma (atopic ornon-atopic) as well as exercise-induced bronchoconstriction,occupational asthma, viral- or bacterial exacerbation of asthma, othernon-allergic asthmas and “wheezy-infant syndrome”, Chronic obstructivepulmonary disease (COPD) including emphysema, adult respiratory distresssyndrome, bronchitis, pneumonia, adult respiratory distress syndrome(ARDS), pigeon fancier's disease, farmers lung;11. Skin diseases such as psoriasis and eczema, dermatitis, sunburn,burns as well as aprains and strains and tissue trauma;12. Vascular and heart diseases which are inflammation-related likeartheriosclerosis including cardiac transplant atherosclerosis,panarteritis nodosa, periarteritis nodosa, arteritis temporalis, Wegnergranulomatosis, giant cell arthritis, reperfusion injury and erythemanodosum, thrombosis (e.g. deep vein thrombosis, renal, hepathic, portalvein thrombosis); coronary artery disease, aneurysm, vascular rejection,myocardial infarction, embolism, stroke, thrombosis including venousthrombosis, angina including unstable angina, coronary plaqueinflammation, bacterial-induced inflammation including Chlamydia-inducedinflammation, viral induced inflammation, and inflammation associatedwith surgical procedures such as vascular grafting including coronaryartery bypass surgery, revascularization procedures includingangioplasty, stent placement, endarterectomy, or other invasiveprocedures involving arteries, veins and capillaries, artery restenosis;13. Diabetes-associated symptoms such as diabetic vasculopathy, diabeticneuropathy, diabetic retinopathy, post capillary resistance or diabeticsymptoms associated with insulitis (e.g. hyperglycemia, diuresis,proteinuria and increased nitrite and kallikrein urinary excretion);14. Benign and malignant tumors and neoplasia including cancer, such ascolorectal cancer, brain cancer, bone cancer, epithelial cell-derivedneoplasia (epithelial carcinoma) such as basal cell carcinoma,adenocarcinoma, gastrointestinal cancer such as lip cancer, mouthcancer, esophageal cancer, small bowel cancer, stomach cancer, coloncancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer,cervical cancer, lung cancer, breast cancer, skin cancer such assquamous cell and basal cell cancers, prostate cancer, renal cellcarcinoma, and other known cancers effecting epithelial cells throughoutthe body; neoplasias like gastrointestinal cancer, Barrett's esophagus,liver cancer, bladder cancer, pancreatic cancer, ovarian cancer,prostate cancer, cervical cancer, lung cancer, breast cancer and skincancer; adenomatous polyps, including familial adenomatous polyposis(FAP) as well preventing polyps from forming in patients at risk of FAP.15. Various other disease states and conditions like epilepsy, septicshock e.g. as antihypovolemic and/or antihypotensive agents, sepsis,osteoporosis, benign prostatic hyperplasia and hyperactive bladder,nephritis, pruritis, vitiligo, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, allergic skin reactions, mixed-vascular and non-vascularsyndromes, septic shock associated with bacterial infections or withtrauma, central nervous system injury, tissue damage and postoperativefever, syndromes associated with itching.

Preferred according to the present invention is the use of a compound offormula I for the treatment and/or prevention of pain; in particularpain that is associated with any one of the diseases or conditionslisted above.

Another aspect of the present invention is a method for the treatmentand/or prevention of above mentioned diseases and conditions, whichmethod comprises the administration of an effective amount of a compoundof formula Ito a human being.

Dosage

The dose range of the compounds of formula I applicable per day isusually from 0.01 to 5000 mg, preferably from 1 to 2000 mg, morepreferably from 5 to 500 mg, most preferably 10 to 250 mg. Each dosageunit may conveniently contain from 2 to 500 mg, preferably 5 to 250 mg.

The actual pharmaceutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the combination will be administered at dosages andin a manner which allows a pharmaceutically effective amount to bedelivered based upon patient's unique condition.

Pharmaceutical Formulations

Suitable preparations for administering the compounds of formula will beapparent to those with ordinary skill in the art and include for exampletablets, pills, capsules, suppositories, lozenges, troches, solutions,syrups, elixirs, sachets, injectables, inhalatives and powders etc. Thecontent of the pharmaceutically active compound(s) should be in therange from 1 to 99 wt.-%, preferably 10 to 90 wt.-%, more preferably 20to 70 wt.-%, of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula I with known excipients, for exampleinert diluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers. Afurther aspect of the invention is a pharmaceutical formulationincluding a compound of formula I in admixture with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

Combination Therapy

The compounds according to the present invention can be combined withother treatment options known to be used in the art in connection with atreatment of any of the indications the treatment of which is in thefocus of the present invention.

Among such treatment options that are considered suitable forcombination with the treatment according to the present inventions are:

-   -   non-steroidal antiinfiammatory drugs (NSAIDs) including COX-2        inhibitors;    -   opiate receptor agonists;    -   Cannabionoid agonists or inhibitors of the endocannabinoid        pathway    -   Sodium channel blockers;    -   N-type calcium channel blockers;    -   serotonergic and noradrenergic modulators;    -   corticosteroids;    -   histamine H1 receptor antagonists;    -   histamine H2 receptor antagonists;    -   proton pump inhibitors;    -   leukotriene antagonists and 5-lipoxygenase inhibitors;    -   local anesthetics;    -   VR1 agonists and antagonists;    -   Nicotinic acetylcholine receptor agonists;    -   P2X3 receptor antagonists;    -   NGF agonists and antagonists or anti-NGF antibodies;    -   NK1 and NK2 antagonists;    -   Bradykinin B1 antagonists    -   CCR2 antagonists    -   NOS or nNOS or eNOS inhibitors    -   NMDA antagonist;    -   potassium channel modulators;    -   GABA modulators;    -   serotonergic and noradrenergic modulators;    -   anti-migraine drugs;    -   neuropathic pain drugs such as pregabaline or duloxetine.        Said list is not considered to have a limiting character.        In the Following Representative Examples of Such Treatment        Options Shall be Given.    -   Non-steroidal antiinfiammatory drugs (NSAI Ds) including COX-2        inhibitors: propionic acid derivatives (alminoprofen,        benoxaprofen, bucloxic acid, carprofen, fenhufen, fenoprofen,        flubiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen,        naproxen, oxaprozin, pirprofen, pranoprofen, suprofen,        tiaprofenic acid, and tioxaprofen), acetic acid derivatives        (indomethacin, acemetacin, alclofenac, clidanac, diclofenac,        fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,        isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin,        and zomepirac), fenamic acid derivatives (meclofenamic acid,        mefenamic acid, and tolfenamic acid), biphenyl-carboxylic acid        derivatives, oxicams (isoxicam, meloxicam, piroxicam, sudoxicam        and tenoxican), salicylates (acetyl salicylic acid,        sulfasalazine) and the pyrazolones (apazone, bezpiperylon,        feprazone, mofebutazone, oxyphenbutazone, phenylbutazone), and        the coxibs (celecoxib, valecoxib, rofecoxib and etoricoxib) and        the like;    -   Antiviral drugs like acyclovir, tenovir, pleconaril, peramivir,        pocosanol and the like.    -   Antibiotic drugs like gentamicin, streptomycin, geldanamycin,        doripenem, cephalexin, cefaclor, ceftazichine, cefepime,        erythromycin, vancomycin, aztreonam, amoxicillin, bacitracin,        enoxacin, mafenide, doxycycline, chloramphenicol and the like;    -   Opiate receptor agonists: morphine, propoxyphene (Darvon),        tramadol, buprenorphin and the like;    -   Glucocorticosteroids such as bethamethasone, budesonide,        dexamethasone, hydrocortisone, methylprednisolone, prednisolone,        prednisone, triamcinolone and deflazacort; immunosuppressive,        immunomodulatory, or cytsostatic drugs inlcuding but not limited        to hydroxychlorquine, D-penicillamine, sulfasalizine, auranofin,        gold mercaptopurine, tacrolimus, sirolimus, mycophenolate        mofetil, cyclosporine, leflunomide, methotrexate, azathioprine,        cyclophosphamide and glatiramer acetate and novantrone,        fingolimod (FTY720), minocycline and thalidomide and the like;    -   anti-TNF antibodies or TNF-receptor antagonists such as but not        limited to Etanercept, Infliximab, Adalimumab (D2E7), CDP 571,        and Ro 45-2081 (Lenercept), or biologic agents directed against        targets such as but not limited to CD-4, CTLA-4, LFA-1, IL-6,        ICAM-1, C5 and Natalizumab and the like;    -   IL-1 receptor antagonists such as but not limited to Kineret;    -   Sodium channel blockers: carbamazepine, mexiletine, lamotrigine,        tectin, lacosamide and the like.    -   N-type calcium channel blockers: Ziconotide and the like.    -   Serotonergic and noradrenergic modulators: paroxetine,        duloxetine, clonidine, amitriptyline, citalopram;    -   Histamine H1 receptor antagonists: bromophtniramint,        chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine,        diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine,        methdiJazine, promethazine, trimeprazine, azatadine,        cyproheptadine, antazoline, pheniramine pyrilamine, astemizole,        terfenadine, loratadine, cetirizine, deslo-ratadine,        fexofenadine and levocetirizine and the like;    -   Histamine H2 receptor antagonists: cimetidine, famotidine and        ranitidine and the like;    -   Proton pump inhibitors: omeprazole, pantoprazole and        esomeprazole and the like;    -   Leukotriene antagonists and 5-lipoxygenase inhibitors:        zafirlukast, mon-telukast, pranlukast and zileuton and the like;    -   Local anesthetics such as ambroxol, lidocaine and the like;    -   Potassium channel modulators: like retigabine;    -   GABA modulators: lacosamide, pregabalin, gabapentin and the        like;    -   Anti-migraine drugs: sumatriptan, zolmitriptan, naratriptan,        eletriptan, telcegepant and the like;    -   NGF antibodies such as RI-724 and the like.

Combination therapy is also possible with new principles for thetreatment of pain e.g. P2X3 antagonists, VR1 antagonists, NK1 and NK2antagonists, NMDA antagonists, mGluR antagonists and the like.

The combination of compounds is preferably a synergistic combination.Synergy, as described for example by Chou and Talalay, Adv. EnzymeRegul. 22:27-55 (1984), occurs when the effect of the compounds whenadministered in combination is greater than the additive effect of thecompounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at suboptimalconcentrations of the compounds. Synergy can be in terms of lowercytotoxicity, increased pharmacological effect, or some other beneficialeffect of the combination compared with the individual components.

EXPERIMENTAL SECTION Preparation of Examples for Compounds of theGeneral Formula I

Unless otherwise stated, one or more tautomeric forms of compounds ofthe examples described hereinafter may be prepared in situ and/orisolated. All tautomeric forms of compounds of the examples describedhereinafter should be considered to be disclosed.

The invention is illustrated by way of the following examples, in whichthe following abbreviations may be employed:

ABBREVIATIONS

-   AcOH acetic acid-   ALOX B aluminium oxide-   aq aqueous-   Boc tert.-butoxycarbonyl-   CE chromatography equipment-   CH cyclohexane-   conc concentrated-   DCM dichloromethane-   DIC N,N′-diisopropylcarbodiimide-   DIPEA N-ethyldiisopropylamine-   DMAP N,N-dimethylaminopyridine-   DMSO dimethylsulphoxide-   DMF N,N-dimethylformamide-   EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   eq. equivalent-   EtOAc ethyl acetate-   Et₂O diethyl ether-   EtOH ethanol-   FA formic acid-   HBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophospate-   HPLC high performance liquid chromatography-   i-PrOH isopropanol-   MeCN acetonitrile-   MeOH methanol-   MS mass spectrometry-   MTBE methyl-tert-butyl ether-   NMP N-Methylpyrrolidinon-   NMR nuclear magnetic resonance-   PE petrol ether-   PPA 1-propylphosphonic-acid cyclic anhydride-   Pd/C 10% Palladium on carbon-   Pt/C Platinum on carbon-   Ra—Ni Raney-Nickel-   RP reversed phase-   rt room temperature-   R_(f) retention factor-   R_(t) retention time-   sat saturated-   TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TCDI thiocarbonyl diimidazole-   TEA triethylamine-   THF tetrahydrofuran-   TFA trifluoroacetic acid-   TLC thin layer chromatography    Analytical Methods

The HPLC/MS data, where specified, were obtained under the followingconditions:

Chromatography Equipment (CE):

CE1:

Agilent 1100 with quarternary pump, Gilson G215 Autosampler, HP diodearray detector.

The diode array detection took place in a wavelength range from 210-550nm

Range of mass-spectrometric detection: m/z 120 to m/z 1000

CE 2:

Waters ZQ2000 MS, Alliance 2695, PDA 2996, 210-500 nm, waters 2700 AS.

Range of mass-spectrometric detection: m/z 120 to m/z 820

CE 3:

Waters ZQ2000 MS, Agilent HP 100, binary pump, waters 2700 AS.

The diode array detection took place in a wavelength range from 210-500nm

Range of mass-spectrometric detection: m/z 120 to m/z 820

CE 4:

Agilent 1200 with binary pump, Agilent MS 6140, HiPALS1367C

The diode array detection took place in a wavelength range from 190-400nm

Range of mass-spectrometric detection: m/z 100 to m/z 1000

CE 5:

Waters ZQ2000 MS, Agilent HP 100, binary pump, Gilson 215 AS.

The diode array detection took place in a wavelength range from 210-500nm

Range of mass-spectrometric detection: m/z 120 to m/z 820

CE 6:

Waters SQD MS, Acquity HPLC.

The diode array detection took place in a wavelength range from 210-500nm

Range of mass-spectrometric detection: m/z 120 to m/z 820

CE 7:

Waters Alliance 2695 Separations Module.

Waters 2487 Dual X Absorbance Detector (detection at 254 nm and 280 nm).

Waters 3100 Mass Detector. Range of mass-spectrometric detection: m/z150 to m/z 1200.

CE 8:

Waters Acquity HPLC system, Waters Acquity TUV Detector (detection at210 nm), Waters Acquity Binary Solvent Manager and Micromas Quattromicro API Mass Spectrometer.

The following methods were used:

Method A:

CE 4 was used.

Mobile phase: E1: water with 0.15% formic acid; E2: acetonitrile

Eluent gradient:

time in min % E1 % E2 flow rate in mL/min 0.0 95 5 1.6 2.25 10 90 1.62.50 10 90 1.6 2.75 90 10 1.6Chromatography column: (column temperature: constant at 25° C.): XBridgeC18, 2.5 μm, 3.0×30 mmMethod B:CE 4 was used.Mobile phase and eluent gradient: As described in method A.Chromatography column: (column temperature: constant at 25° C.): SunfireC18, 2.5 μm, 3.0×30 mmMethod C:CE 2 was used.Mobile phase: E1: water with 0.1% TFA; E2: acetonitrile with 0.08% TFAEluent gradient:

time in min % E1 % E2 flow rate in mL/min 0.0 95 5 1.5 2.00 0 100 1.53.00 0 100 1.5 3.40 95 5 1.5Chromatography column: (column temperature: constant at 40° C.): Waterssunfire C18, 3.5 μm, 4.6×50 mmMethod D:CE 3 was used.Mobile phase: E1: water with 0.032% NH₃, E2: MeOHEluent gradient:

time in min % E1 % E2 flow rate in mL/min 0.0 95 5 1.5 2.00 0 100 1.5Chromatography column: (column temperature: constant at 40° C.): WatersXBridge C18, 3.5 μm, 4.6×50 mmMethod E:CE 4 was used.Mobile phase: E1: water with 0.15% formic acid; E2: acetonitrileEluent gradient:

time in min % E1 % E2 flow rate in mL/min 0.00 95 5 1.6 2.00 50 50 1.62.25 10 90 1.6 2.50 10 90 1.6 2.75 95 5 1.6Chromatography column: (column temperature: constant at 25° C.): SunfireC18, 2.5 μm, 3.0×30 mmMethod F:CE 4 was used.Mobile phase: E1: water with 0.15% formic acid; E2: acetonitrileEluent gradient:

time in min % E1 % E2 flow rate in mL/min 0.00 95 5 1.6 1.00 10 90 1.62.50 10 90 1.6 2.75 95 5 1.6Chromatography column: (column temperature: constant at 25° C.): SunfireC18, 2.5 μm, 3.0×30 mmMethod G:CE 4 was used.Mobile phase and eluent gradient: as described in Method E.Chromatography column: (column temperature: constant at 25° C.): ZorbaxStable Bond C18, 1.8 μm, 3.0×30 mmMethod H:CE 4 was used.Mobile phase and eluent gradient: As described in Method A.Chromatography column: (column temperature: constant at 25° C.): ZorbaxStable Bond C18, 1.8 μm, 3.0×30 mmMethod I:CE 4 was used.Mobile phase: E1: water with 0.15% formic acid; E2: acetonitrileEluent gradient:

time in min % E1 % E2 flow rate in mL/min 0.0 95 5 1.6 2.00 10 90 1.65.00 10 90 1.6 5.50 90 10 1.6Chromatography column: (column temperature: constant at 25° C.): ZorbaxStable Bond C18, 3.5 μm, 4.6×75 mmMethod J:CE 3 was used.Mobile phase: E1: water with 0.1% TFA; E2: acetonitrile with 0.08% TFAEluent gradient:

time in min % E1 % E2 flow rate in mL/min 0.0 95 5 1.5 2.00 0 100 1.52.50 0 100 1.5 2.60 95 5 1.5Chromatography column: (column temperature: constant at 40° C.): Waterssunfire C18, 3.5 μm, 4.6×50 mmMethod K:CE 3 was used.Mobile phase: E1: water with 0.15% HCOOH, E2: MeOHEluent gradient and column as in method D:Method L:CE 5 was used.Mobile phase: E1: water with 0.1% TFA; E2: acetonitrile with 0.1% TFAEluent gradient:

time in min % E1 % E2 flow rate in mL/min 0.0 95 5 1.5 2.00 0 100 1.52.49 0 100 1.5 2.50 95 5 1.5Chromatography column: (column temperature: constant at 40° C.): Waterssunfire C18, 3.5 μm, 4.6×50 mmMethod M:CE 5 was used.Mobile phase: E1: water with 0.032% NH₃; E2: acetonitrileEluent gradient:

time in min % E1 % E2 flow rate in mL/min 0.0 95 5 1.3 2.00 0 100 1.32.50 0 100 1.3 2.60 95 5 1.3Chromatography column: (column temperature: constant at 60° C.): WatersXBridge C18, 1.7 μm, 2.1×50 mmMethod N:CE 7 was used.Mobile phase: E1: water with 0.01% TFA; E2: acetonitrile with 0.01% TFAEluent gradient:

time in min % E1 % E2 flow rate in mL/min 0.00 90 10 0.2 15.00 5 95 0.225.00 5 95 0.2 25.10 90 10 0.2Chromatography column: (column temperature: constant at 30° C.):Atlantis dC18, 5 μm, 2.1×50 mmMethod O:CE 7 was used.E1: water with 0.01% TFA; E2: acetonitrile with 0.01% TFAEluent gradient:

time in min % E1 % E2 flow rate in mL/min 0.00 90 10 0.2 15.00 5 95 0.220.00 5 95 0.2 20.10 90 10 0.2 25.00 90 10 0.2Chromatography column: (column temperature: constant at 30° C.): XBridgeC18, 3.5 μm, 2.1×50 mmMethod P:CE 8 was used.Mobile phase: E1: water with 0.1% HCOOH; E2: acetonitrile with 0.1%HCOOHEluent gradient:

time in min % E1 % E2 flow rate in mL/min 0.00 95 5 0.2 10.00 2 98 0.215.00 2 98 0.2 15.50 95 5 0.2 20.00 95 5 0.2Chromatography column: (column temperature: constant at 30° C.): AcquityHPLC BEH C18, 1.7 μm, 2.1×50 mmMethod O:CE 5 was used.Mobile phase: E1: water with 0.1% TFA; E2: MeOHEluent gradient:

time in min % E1 % E2 flow rate in mL/min 0.0 80 20 2.0 1.70 0 100 2.02.50 0 100 2.0 2.60 80 20 2.0Chromatography column: (column temperature: constant at 60° C.): Waterssunfire C18, 3.5 μm, 4.6×50 mm

In the mass spectra in general only the m/z-peak of the main isotope iscited. For all compounds where mass spectra data is given, the isotopepatterns are in analogy to the natural occurrence of the elements whichare present in the given compound.

Example 12-Amino-N-{4-chloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzyl}-3,3,3-trifluoro-2-methylpropanamide

(a) Tert-butyl 4-chloro-3-nitrobenzylcarbamate

TEA (3.12 mL, 22.4 mmol) followed by DMAP (0.14 g, 1.1 mmol) were addedto (4-chloro-3-nitrophenyl)methanamine hydrochloride (5.00 g, 22.4 mmol)in DCM (30 mL). The mixture was cooled to 0° C. and BOC-anhydride (5.87g, 26.9 mmol) in DCM (15 mL) was added. After stirring at 0° C. for 30min and further 18 h at rt the reaction mixture was poured into ammonia(10%). The mixture was extracted with DCM. The combined extracts werewashed with brine, dried over Na₂SO₄ and concentrated to give thesub-title compound.

Yield: 5.66 g (88%). R_(f)(TLC): 0.75 (silica gel, DCM:EtOH 98:2)

(b) Tert-butyl 3-amino-4-chlorobenzylcarbamate

Sat. aq. NH₄Cl (50 mL) followed by iron powder (5.51 g, 98.7 mmol) wereadded at rt to a mixture of tert-butyl 4-chloro-3-nitrobenzylcarbamate(5.66 g, 19.7 mmol) and EtOH (50 mL). After stirring for 4 h at 80° C.,4 h at 90° C. and at rt overnight the reaction mixture was filteredthrough celite and washed with EtOAc. The aq. layer was extracted withEtOAc. The combined extracts were washed with brine, dried over Na₂SO₄and concentrated to give the sub-title compound.

Yield: 5.02 g (99%). R_(f)(TLC): 0.33 (silica gel, DCM:EtOH 98:2). MSm/z: 257 [M+H]⁺.

(c) Tert-butyl 4-chloro-3-isothiocyanatobenzylcarbamate

Tert-butyl 3-amino-4-chlorobenzylcarbamate (2.57 g, 10.0 mmol) was addedto a mixture of 1,1′-thiocarbonyldi-2-pyridone (2.55 g, 11.0 mmol) andDCM (90 mL) and it was stirred at rt for 4 h. The mixture was dilutedwith DCM and filtered over silica gel. The organic layer wasconcentrated to give the sub-title compound.

Yield: 2.73 g (91%). R_(f)(TLC): 0.88 (silica gel, PE:EtOAc 1:1). MSm/z: 297 [M−H]⁻.

(d) 4,5-Dichloro-N-methyl-2-nitroaniline

1,2-Dichloro-4-fluoro-5-nitrobenzene (5.00 g, 23.8 mmol) in DMF (5.0 mL)was added to methylamine (10% in toluene, 80.0 g, 258 mmol) and stirredat rt overnight. The reaction mixture was filtered through a pad of ALOXB, washed with DMF/MeOH and concentrated to give the sub-title compound.

Yield: 5.22 g (99%). HPLC-method C: R_(t)=2.70 min. MS m/z: 221 [m]⁺.

(e)4-Chloro-N-methyl-2-nitro-5-(3-(trifluoromethyl)piperidin-1-yl)aniline

3-(Trifluoromethyl)piperidine (0.69 g, 4.5 mmol) followed by potassiumcarbonate (1.25 g, 9.1 mmol) were added to4,5-dichloro-N-methyl-2-nitroaniline (1.00 g, 4.5 mmol) in DMF (15 mL).The reaction mixture was stirred 5 h at 80° C. and overnight at 70° C.After addition of further 1.5 eq of potassium carbonate the mixture wasstirred 2 h at rt and 2 days at 100° C. The reaction mixture wasfiltered through a pad of ALOX B and concentrated. The crude waspurified by chromatography to give the sub-title compound.

Yield: 1.01 g (66%). R_(f)(TLC): 0.36 (silica gel, CH:EtOAc 5:1).HPLC-method C: R_(t)=2.94 min.

MS m/z: 336 [M−H]⁻.

(f) 5-Chloro-2-methylamino-4-(3-(trifluoromethyl)piperidin-1-yl)aniline

A mixture of4-chloro-N-methyl-2-nitro-5-(3-(trifluoromethyl)piperidin-1-yl)aniline(250 mg, 0.7 mmol), THF (6 mL), MeOH (6 mL) and Pt/C (50 mg) was stirredfor 4 h at 35° C. under a hydrogen atmosphere (3.2 bar). The catalystwas removed by filtration and the mixture was concentrated to give thesub-title compound.

Yield: 205 mg (90%). HPLC-method C: R_(t)=2.05 min. MS m/z: 308 [M+H]⁺.

(g) Tert-butylN-{4-chloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzyl}-carbamate

Tert-butyl 4-chloro-3-isothiocyanatobenzylcarbamate (938 mg, 3.1 mmol)was added to5-chloro-2-methylamino-4-(3-(trifluoromethyl)piperidin-1-yl)aniline (920mg, 3.0 mmol) in MeCN (20 mL). The mixture was stirred for 4 h at rt,then EDC (582 μL, 3.3 mmol) was added and it was stirred overnight. Thereaction mixture was purified by chromatography to give the sub-titlecompound.

Yield: 700 mg (41%). HPLC-method C: R_(t)=2.34 min. MS m/z: 572 [m]⁺.

(h)4-Chloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzylamine

4 M HCl in dioxane (20 mL) was added to tert-butylN-{4-chloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzyl}-carbamate(700 mg, 1.2 mmol) in dioxane (20 mL). The reaction mixture was stirredat rt for 2 h then diluted with water and aq. K₂CO₃-solution and stirredfor 1 h at rt. The mixture was concentrated, filtered and the filtercakewas washed with water and dried to give the sub-title compound.

Yield: 570 mg (99%). HPLC-method C: R_(t)=1.83 min. MS m/z: 472 [M+H]⁺.

(i)2-Amino-N-{4-chloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzyl}-3,3,3-trifluoro-2-methylpropanamide

TBTU (106 mg, 0.3 mmol) followed by TEA (126 μL, 0.9 mmol) were added to2-amino-3,3,3-trifluoro-2-methylpropanoic acid (57 mg, 0.4 mmol) in DMF(2 mL). After 5 min at rt a mixture of4-chloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzylamine(142 mg, 0.3 mmol) and DMF (2 mL) was added to the reaction mixture andstirred at rt overnight. The reaction mixture was purified bychromatography to give the title compound.

Yield: 104 mg (57%). HPLC-method D: R_(t)=2.77 min. MS m/z: 611 [M+H]⁺.

Example 2N-{4-Chloro-3-[6-chloro-5-(3,3-difluoropyrrolidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzyl}-2,2-dimethyl-propionamide

(a) N-(4-Chloro-3-nitrobenzyl)-2,2-dimethyl-propionamide

TEA (8.00 mL, 57.5 mmol) followed by pivaloyl chloride (2.80 mL, 22.8mmol) in THF (25 mL) were added to 4-chloro-3-nitrobenzylaminehydrochloride (5.00 g, 22.4 mmol) in THF (100 mL). The reaction mixturewas diluted with THF and stirred at rt for 1.5 h. The mixture wasfiltered and washed. The filtrate was concentrated to give the sub-titlecompound.

Yield: 5.92 g (98%). HPLC-method A: R_(f)=1.911 min. MS m/z: 271 [M+H]⁺.

(b) N-(3-Amino-4-chlorobenzyl)-2,2-dimethyl-propionamide

A mixture of N-(4-chloro-3-nitrobenzyl)-2,2-dimethyl-propionamide (5.92g, 21.9 mmol), THF (150 mL) and Ra—Ni (1.50 g) was stirred for 2 days atRT under a hydrogen atmosphere (3.0 bar). The catalyst was removed byfiltration and the mixture was concentrated. The crude was purified bychromatography to give the sub-title compound.

Yield: 4.31 g (82%). R_(f)(TLC): 0.68 (silica gel, DCM:EtOH 9:1). MSm/z: 241 [M+H]⁺.

(c) N-(4-Chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide

1,1′-Thiocarbonyldi-2-pyridone (2.12 g, 9.1 mmol) was added to a mixtureof N-(3-amino-4-chlorobenzyl)-2,2-dimethyl-propionamide (2.00 g, 8.3mmol) and DCM (60 mL) and stirred at rt for 1.5 h. The mixture wasfiltered over silica gel. The organic layer was concentrated to give thesub-title compound.

Yield: 1.48 g (63%). R_(f)(TLC): 0.73 (silica gel, DCM:EtOH 9:1).

(d) 4-Chloro-5-(3,3-difluoropyrrolidin-1-yl)-2-nitroaniline

3,3-Difluoropyrrolidine hydrochloride (3.12 g, 21.7 mmol) followed bypotassium carbonate (4.00 g, 29.0 mmol) were added to4,5-dichloro-2-nitroaniline (3.00 g, 14.5 mmol) in DMF (60 mL). Thereaction mixture was stirred at 130° C. over the weekend. After coolingthe reaction mixture was poured into ice-water and extracted with EtOAc.The combined organic layers were washed with water, dried, concentratedand the crude was purified by chromatography to give the sub-titlecompound.

Yield: 1.73 g (31%). R_(f)(TLC): 0.33 (silica gel, PE:EtOAc 7:3). MSm/z: 278 [M+H]⁺.

(e) 4-Chloro-5-(3,3-difluoropyrrolidin-1-yl)benzene-1,2-diaminedihydrochloride

A mixture of 4-chloro-5-(3,3-difluoropyrrolidin-1-yl)-2-nitroaniline(300 mg, 1.1 mmol), THF (10 mL) and Pd/C (20 mg) was stirred for 1.5days at RT under a hydrogen atmosphere (3.0 bar). The catalyst wasremoved by filtration. To the filtrate was added 4 M HCl in dioxane (10mL). The mixture was concentrated and used in the next step withoutfurther purification.

Yield: 340 mg (98%). MS m/z: 248 [M+H]⁺. HPLC-method A: R_(t)=1.40 min

(f)N-{4-Chloro-3-[2-amino-5-chloro-4-(3,3-difluoropyrrolidin-1-yl)phenyl)thioureido]-benzyl}-2,2-dimethyl-propionamide

4-Chloro-5-(3,3-difluoropyrrolidin-1-yl)benzene-1,2-diaminedihydrochloride (340 mg, 1.1 mmol) was added toN-(4-chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide (300 mg,1.1 mmol) in MeCN (10 mL) and stirred at rt overnight. After addition ofDIPEA (0.41 μL, 2.3 mmol) the reaction mixture was stirred at rt for 4.5h. The mixture was concentrated. The crude was purified bychromatography to give the sub-title compound.

Yield: 140 mg (25%). R_(f)(TLC): 0.47 (silica gel, DCM:EtOH 9:1).

(g)N-{4-Chloro-3-[6-chloro-5-(3,3-difluoropyrrolidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzyl}-2,2-dimethyl-propionamide

DIC (50 μL, 0.3 mmol) was added to a mixture ofN-{4-chloro-3-[2-amino-5-chloro-4-(3,3-difluoropyrrolidin-1-yl)phenyl)thioureido]-benzyl}-2,2-dimethyl-propionamide(140 mg, 0.3 mmol) and MeCN (4 mL). After 1.5 h at 60° C. the reactionmixture was allowed to cool and was concentrated. The crude was purifiedby chromatography to give the title compound.

Yield: 22 mg (17%). R_(f)(TLC): 0.33 (silica gel, DCM:EtOH 9:1). MS m/z:496 [M+H]⁺.

Example 3N-{4-Chloro-3-[5-chloro-6-(3-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

(a) 4-Chloro-5-(3-dimethylaminomethyl-pyrrolidin-1-yl)-2-nitroaniline

Potassium carbonate (500 mg, 3.6 mmol) was added to a mixture of3-dimethylaminomethyl-pyrrolidine (450 mg, 3.5 mmol) and4,5-dichloro-2-nitroaniline (500 mg, 2.4 mmol) in DMSO (5 mL). Thereaction mixture was stirred at 120° C. overnight, diluted with EtOAcand washed with water and brine. The organic layer was dried over Na₂SO₄and concentrated.

Yield: 630 mg (87%). R_(f)(TLC): 0.15 (silica gel, DCM:EtOH 95:5).HPLC-method B: R_(t)=1.28 min. MS m/z: 299 [M+H]⁺.

(b)4-Chloro-5-(3-dimethylaminomethyl-pyrrolidin-1-yl)-benzene-1,2-diamine

A mixture of4-chloro-5-(3-dimethylaminomethyl-pyrrolidin-1-yl)-2-nitroaniline (630mg, 2.1 mmol), EtOAc (20 mL) and Ra—Ni (150 mg) was stirred for 2 daysat rt under a hydrogen atmosphere (3.0 bar). The catalyst was removed byfiltration and the filtrate was concentrated. The crude was purified bychromatography to give the sub-title compound.

Yield: 480 mg (85%). R_(f)(TLC): 0.50 (silica gel, DCM:EtOH:NH₄OH80:20:2). HPLC-method E: R_(t)=0.11 min. MS m/z: 269 [M+H]⁺.

(c)N-{4-Chloro-3-[5-chloro-6-(3-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-carbamicacid tert-butyl ester

(4-Chloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (111mg, 0.4 mmol) was added to4-chloro-5-(3-dimethylaminomethyl-pyrrolidin-1-yl)-benzene-1,2-diamine(100 mg, 0.4 mmol) in DMF (3 mL). The mixture was stirred at rtovernight, DIC (62.4 μL, 0.4 mmol) was added and stirring was continuedat 80° C. for 3 h. The mixture was concentrated and the crude waspurified by chromatography to give the sub-title compound.

Yield: 150 mg (76%). R_(f)(TLC): 0.30 (silica gel, DCM:EtOH:NH₄OH90:10:1). HPLC-method F: R_(t)=1.01 min. MS m/z: 533 [M+H]⁺.

(d)4-Chloro-3-[5-chloro-6-(3-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine

6 M aq. HCl-solution (1.0 ml) was added toN-{4-chloro-3-[5-chloro-6-(3-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-carbamicacid tert-butyl ester (130 mg, 0.2 mmol) in THF (2 mL) and stirred at50° C. for 1 h. The reaction mixture was concentrated to give thesub-title compound.

Yield: 160 mg. R_(f)(TLC): 0.35 (silica gel, DCM:EtOH:NH₄OH 80:20:2).HPLC-method E: R_(t)=0.20 min. MS m/z: 433 [M+H]⁺.

(e)N-{4-Chloro-3-[5-chloro-6-(3-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

Pivaloyl chloride (10 μL, 0.1 mmol) was added to a mixture of4-chloro-3-[5-chloro-6-(3-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]lpenzylamine(60 mg) and TEA (150 μL, 1.1 mmol) in THF (5 mL) and stirred at rtovernight. The reaction mixture was diluted with EtOAc and washed withsat.aq. NaHCO₃. The organic layer was dried over Na₂SO₄ andconcentrated. The crude was purified by chromatography to give the titlecompound.

Yield: 30 mg (56%). R_(f)(TLC): 0.85 (silica gel, DCM:EtOH:NH₄OH80:20:2). HPLC-method E: R_(t)=0.45 min. MS m/z: 517 [M+H]⁺.

Example 4N-{3-[6-(5-Aza-spiro[2.4]hept-5-yl)-5-chloro-1H-benzimidazol-2-ylamino]-4-chloro-benzyl}-2,2-dimethyl-propionamide

(a) 5-(5-Aza-spiro[2.4]hept-5-yl)-4-chloro-2-nitro-phenylamine

The sub-title compound was prepared from 4,5-dichloro-2-nitroaniline(470 mg, 2.3 mmol), 5-aza-spiro[2.4]heptane (320 mg, 3.3 mmol) andpotassium carbonate (470 mg, 3.4 mmol) in DMSO (5 mL) in analogy toexample 3, step (a). Yield: 550 mg (91%). R_(f)(TLC): 0.85 (silica gel,DCM:EtOH 99:1). HPLC-method F: R_(f)=1.01 min. MS m/z: 533 [2M+H]⁺.

(b) 4-(5-Aza-spiro[2.4]hept-5-yl)-5-chloro-benzene-1,2-diamine

A mixture of 5-(5-aza-spiro[2.4]hept-5-yl)-4-chloro-2-nitro-phenylamine(550 mg, 2.1 mmol), EtOAc (20 mL) and Ra—Ni (150 mg) was stirred for 21h at RT under a hydrogen atmosphere (3 bar). After addition of furthercatalyst the hydrogenation was continued at rt for 7 h. The catalyst wasremoved by filtration. The filtrate was acidified with 1.25 M HCl inEtOH (6 mL) and concentrated to give the sub-title compound.

Yield: 620 mg. R_(f)(TLC): 0.05 (silica gel, DCM:EtOH 99:1). HPLC-methodF: R_(f)=0.77 min. MS m/z: 238 [M+H]⁺.

(c){3-[6-(5-Aza-spiro[2.4]hept-5-yl)-5-chloro-1H-benzimidazol-2-ylamino]-4-chloro-benzyl}-carbamicacid tert-butyl ester

TEA (130 μL, 0.9 mmol) followed by4-(5-aza-spiro[2.4]hept-5-yl)-5-chloro-benzene-1,2-diamine (80 mg) wereadded to (4-chloro-3-isothiocyanato-benzyl)-carbamic acid tert-butylester (example 1, step (c), 69 mg, 0.2 mmol) in DMF (3 mL). The reactionmixture was stirred at rt overnight, then concentrated and purified bychromatography to give the sub-title compound.

Yield: 60 mg (52%). R_(f)(TLC): 0.40 (silica gel, DCM:EtOH 95:5).HPLC-method F: R_(f)=1.25 min. MS m/z: 502 [M+H]⁺.

(d)3-[6-(5-Aza-spiro[2.4]hept-5-yl]-5-chloro-1H-benzimidazol-2-ylamino]-4-chloro-benzylamine

The sub-title compound was prepared in analogy to example 3, step (d)from{3-[6-(5-aza-spiro[2.4]hept-5-yl)-5-chloro-1H-benzimidazol-2-ylamino]-4-chloro-benzyl}-carbamicacid tert-butyl ester (50 mg, 0.1 mmol) and 6 M aq. HCl (0.40 mL) in THF(2 mL).

Yield: 60 mg. R_(f)(TLC): 0.25 (silica gel, DCM:EtOH:NH₄OH 90:10:1).

(e)N-{3-[6-(5-Aza-spiro[2.4]hept-5-yl)-5-chloro-1H-benzimidazol-2-ylamino]-4-chloro-benzyl}-2,2-dimethyl-propionamide

The sub-title compound was prepared from3-[6-(5-aza-spiro[2.4]hept-5-yl)-5-chloro-1H-benzimidazol-2-ylamino]-4-chloro-benzylamine(60 mg, 0.1), pivaloyl chloride (20 μL, 0.1 mmol) and TEA (160 μL, 1.1mmol) in THF (5 mL) in analogy to example 3, step (e).

Yield: 40 mg. R_(f)(TLC): 0.80 (silica gel, DCM:EtOH:NH₄OH 90:10:1).HPLC-method G: R_(t)=1.36 min. MS m/z: 486 [M+H]⁺.

Example 5N-{2,4-Dichloro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

(a) 3-Acetylamino-2,4-dichloro-benzoic acid

Water (110 mL) was added to N-(2,6-dichloro-3-methyl-phenyl)-acetamide(13 g, 59 mmol) in pyridine (30 mL). The mixture was heated to 70° C.and KMnO₄ (47 g, 298 mmol) was cautiously added portionwise. After 6 hat reflux the reaction mixture was filtered through a pad of celite andwashed with hot water. The filtrate was cooled to rt, concentrated andslowly acidified with 6 M aq. HCl solution. The mixture was cooled in anice bath, filtered and the filtercake was washed with cold water anddried to give the sub-title compound.

Yield: 11.6 g (78%). R_(f)=0.1 (silica gel, DCM:EtOH 9:1). MS m/z: 248[M+H]⁺.

(b) 3-Amino-2,4-dichloro-benzoic acid

3-Acetylamino-2,4-dichloro-benzoic acid (21.0 g, 84.6 mmol) was stirredin 6 M aq. HCl-solution (120 mL) and acetic acid (250 mL) at reflux for24 h. The reaction mixture was cooled, concentrated, diluted with waterand concentrated again. The residue was diluted with water, stirredunder cooling and filtered. The filtercake was washed and dried to givethe sub-title compound.

Yield: 16.8 g (96%). MS m/z: 204 [M−H]⁻. HPLC-method C: R_(t)=1.46 min.

(c) 3-Amino-2,4-dichloro-benzamide

(1-Chloro-2-methyl-propenyl)-dimethyl-amine (16.1 mL, 116 mmol) wasadded to 3-amino-2,4-dichloro-benzoic acid (20.0 g, 97.1 mmol) in THF(320 mL). After 4 h at rt the mixture was added dropwise to conc. NH₃(320 mL) and stirred at rt overnight. The reaction mixture wasconcentrated, cooled and filtered. The filtercake was dried to give thesub-title compound.

Yield: 17.4 g (87%). MS m/z: 205 [M+H]⁺. HPLC-method C: R_(t)=1.19 min.

(d) 3-Amino-2,4-dichloro-benzylamine

3-Amino-2,4-dichloro-benzamide (2.00 g, 9.8 mmol) in THF (45 mL) wasadded dropwise to LiAlH₄ (1 M in THF, 24.4 mL) in THF (45 mL). Thereaction mixture was stirred for 1 h at rt and 10 h at reflux. ExcessLiAlH₄ was carefully destroyed under cooling as described by L. F.Fieser & M. Fieser Vol 1, p 584 Wiley 1967. After 30 min the mixture wasfiltered and the filtrate was concentrated to give the sub-titlecompound.

Yield: 1.85 g (99%). R_(t)=0.12 (silica gel, DCM:EtOH 95:5). MS m/z: 191[M+H]⁺.

(e) N-(3-Amino-2,4-dichloro-benzyl)-2,2-dimethyl-propionamide

3-Amino-2,4-dichloro-benzylamine (2.28 g, 11.9 mmol) was added to amixture of 2,2-dimethyl-propionic acid chloride (1.47 mL, 11.9 mmol) andTEA (4.14 mL, 29.8 mmol) in THF (90 mL) and it was stirred for 3 h. Thereaction mixture was concentrated, diluted with EtOAc, washed with 5%aq. NaHCO₃ solution and water, dried with Na₂SO₄ filtered andconcentrated to give the sub-title compound.

Yield: 3.1 g (94%). R_(t)=0.61 (silica gel, DCM:EtOH 95:5).

(f) N-(2,4-Dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide

1,1′-Thiocarbonyldi-2-pyridone (4.87 g, 21 mmol) was added to a mixtureof N-(3-amino-2,4-dichloro-benzyl)-2,2-dimethyl-propionamide (5.50 g, 20mmol) and dioxane (200 mL) and stirred at rt for 2 h and at reflux for 8h. The mixture was concentrated, diluted with DCM and filtered oversilica gel. The filtrate was concentrated to give the sub-titlecompound.

Yield: 6.00 g (95%). HPLC-method B: R_(t)=1.58 min. MS m/z: 318 [M+H]⁺.

(g)4-Chloro-N-methyl-2-nitro-5-(4-trifluoromethyl-piperidin-1-yl)aniline

The sub-title compound was prepared from4,5-dichloro-2-nitro-N-methyl-aniline (820 mg, 3.7 mmol),4-trifluoromethyl-piperidine (680 mg, 4.5 mmol) and potassium carbonate(770 mg, 5.6 mmol) in DMSO (10 mL) in analogy to example 3, step (a).

Yield: 1.07 g (85%). R_(f)(TLC): 0.15 (silica gel, PE:EtOAc 9:1). MSm/z: 338 [M+H]⁺.

HPLC-method G: R_(t)=1.70 min

(h) 5-Chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline

A mixture of4-chloro-N-methyl-2-nitro-5-(4-trifluoromethyl-piperidin-1-yl)aniline(1.07 g, 3.2 mmol), THF (20 mL), MeOH (30 mL) and Pt/C (100 mg) wasstirred for 6 h at rt under a hydrogen atmosphere (3 bar). The catalystwas removed by filtration and the mixture was concentrated to give thesub-title compound.

Yield: 1.00 g. R_(f)(TLC): 0.25 (silica gel, DCM). HPLC-method G:R_(t)=1.30 min. MS m/z: 308 [M+H]⁺.

(i)N-{2,4-Dichloro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

N-(2,4-Dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (120mg, 0.4 mmol) was added to(4-chloro-2-methylamino-5-(4-trifluoromethyl-piperidin-1-yl)aniline (110mg, 0.4 mmol) in DMF (2 mL). After 3 h at rt DIC (74 μL, 0.5 mmol) wasadded to the reaction mixture and it was stirred at 80° C. for 5.5 h.Additional DIC (40 μL, 0.3 mmol) was added and stirring was continued at100° C. overnight. The reaction mixture was concentrated and the crudewas purified by chromatography to give the title compound.

Yield: 140 mg (65%). R_(f)(TLC): 0.35 (silica gel, DCM:EtOH 95:5). MSm/z: 590 [M+H]⁺.

HPLC-method G: R_(t)=1.44 min.

Example 6N-{4-Chloro-3-[5-chloro-6-(2-dimethylcarbamoyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

(a) 4-Chloro-5-(2-dimethylcarbamoyl-pyrrolidin-1-yl)-2-nitroaniline

Potassium carbonate (1.00 g, 7.3 mmol) was added to a mixture ofpyrrolidine-2-carboxylic acid dimethylamide (1.00 g, 7.0 mmol) and4,5-dichloro-2-nitroaniline (1.00 g, 4.8 mmol) in DMSO (6 mL). Thereaction mixture was stirred at 120° C. for 2.5 h, diluted with EtOAcand washed with water and sat.aq. NaCl. The organic layer was dried overNa₂SO₄, concentrated and the crude was purified by chromatography togive the sub-title compound.

Yield: 1.18 g (78%). R_(f)(TLC): 0.15 (silica gel, DCM:EtOH 98:2). MSm/z: 313 [M+H]⁺.

(b) 1-(4,5-Diamino-2-chloro-phenyl)-pyrrolidine-2-carboxylic aciddimethylamide

Tin dichloride dihydrate (710 mg, 3.1 mmol) was added to4-chloro-5-(2-dimethylcarbamoyl-pyrrolidin-1-yl)-2-nitroaniline (200 mg,0.6 mmol) in EtOAc (5 mL). The reaction mixture was stirred at refluxfor 3 h, cooled and poured into sat.aq. NaHCO₃-solution. The mixture wasfiltered through a pad of celite. The organic layer was dried overNa₂SO₄ and concentrated to give the sub-title compound.

Yield: 75 mg (42%). R_(f)(TLC): 0.40 (silica gel, DCM:EtOH:NH₄OH90:10:1). MS m/z: 283 [M+H]⁺. HPLC-method F: R_(f)=0.84 min.

(c)N-{4-Chloro-3-[5-chloro-6-(2-dimethylcarbamoyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

N-(4-Chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide (75 mg,0.3 mmol), which was prepared as described in example 2 step (c), wasadded to 1-(4,5-diamino-2-chloro-phenyl)-pyrrolidine-2-carboxylic aciddimethylamide (75 mg, 0.3 mmol) in DMF (2 mL) and stirred at rtovernight. DIC (45 μL, 0.3 mmol) was added to the reaction mixture andstirring was continued for 5 h at 80° C. The mixture was concentratedand the crude was purified by chromatography to give the title compound.

Yield: 60 mg (43%). R_(f)(TLC): 0.20 (silica gel, DCM:EtOH 95:5). MSm/z: 531 [M+H]⁺. HPLC-method F: R_(t)=1.09 min.

Example 7N-{4-Chloro-3-[5-chloro-6-(2-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

(a) 4-Chloro-5-(2-dimethylaminomethyl-pyrrolidin-1-yl)-2-nitroaniline

The sub-title compound was prepared from2-dimethylaminomethyl-pyrrolidine (270 mg, 2.1 mmol),4,5-dichloro-2-nitroaniline (300 mg, 1.5 mmol) and potassium carbonate(300 mg, 2.2 mmol) in DMSO (3 mL) in analogy to the method described inexample 3 step (a).

Yield: 220 mg (51%). R_(f)(TLC): 0.05 (silica gel, DCM:EtOH 99:1)

(b)4-Chloro-5-(2-dimethylaminomethyl-pyrrolidin-1-yl)-benzene-1,2-diamine

A mixture of4-chloro-5-(2-dimethylaminomethyl-pyrrolidin-1-yl)-2-nitroaniline (150mg, 0.5 mmol), EtOAc (10 mL) and Ra—Ni (50 mg) was stirred for 19 h atrt under a hydrogen atmosphere (3.0 bar). Further catalyst was added andthe hydrogenation was continued for 6 h at 40° C. The catalyst wasremoved by filtration, the filtrate was acidified with 1.25 M HCl inEtOH and concentrated to give the sub-title compound.

Yield: 180 mg. R_(f)(TLC): 0.15 (silica gel, DCM:EtOH:NH₄OH 90:10:1). MSm/z: 269 [M+H]⁺.

(c){4-Chloro-3-[5-chloro-6-(2-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-carbamicacid tert-butyl ester

(4-Chloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (68mg, 0.2 mmol) followed by TEA (160 μL, 1.2 mmol) were added to4-chloro-5-(2-dimethylaminomethyl-pyrrolidin-1-yl)-benzene-1,2-diamine(95 mg) in DMF (3 mL). The mixture was stirred at rt for 4 h and thenpurified by chromatography to give the sub-title compound.

Yield: 20 mg (16%). R_(f)(TLC): 0.30 (silica gel, DCM:EtOH:NH₄OH90:10:1). HPLC-method F: R_(t)=1.01 min. MS m/z: 533 [M+H]⁺.

(d)4-Chloro-3-[5-chloro-6-(2-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine

The sub-title compound was prepared from{4-chloro-3-[5-chloro-6-(2-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-carbamicacid tert-butyl ester (20 mg, 0.04 mmol) and 6 M aq. HCl-solution (1.0ml) in THF (2 mL) in analogy to example 3 step (d).

Yield: 30 mgR_(f)(TLC): 0.40 (silica gel, DCM:EtOH:NH₄OH 80:20:2).

(e)N-{4-Chloro-3-[5-chloro-6-(2-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

The title compound was prepared analogously to example 3 step (e) from4-chloro-3-[5-chloro-6-(2-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine(30 mg), pivaloyl chloride (10 μL, 0.06 mmol) and TEA (70 μL, 0.54 mmol)in THF (2 mL).

Yield: 20 mg (75%). R_(f)(TLC): 0.90 (silica gel, DCM:EtOH:NH₄OH80:20:2). HPLC-method E: R_(t)=1.42 min. MS m/z: 517 [M+H]⁺.

Example 8N-{4-Chloro-3-[5-chloro-6-(3-cyano-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

(a) 1-(5-Amino-2-chloro-4-nitro-phenyl)-pyrrolidine-3-carbonitrile

Potassium carbonate (2.93 g, 21.3 mmol) was added to a mixture ofpyrrolidine-3-carbonitrile hydrochloride (1.41 g, 10.6 mmol) and4,5-dichloro-2-nitroaniline (2.00 g, 9.7 mmol) in DMF (8 mL). Thereaction mixture was stirred at 120° C. overnight, diluted with EtOAcand washed with water and brine. The organic layer was dried overNa₂SO₄, concentrated and the crude was purified by chromatography togive the sub-title compound.

Yield: 1.18 g (78%). R_(f)(TLC): 0.25 (silica gel, DCM). MS m/z: 267[M+H]⁺. HPLC-method G: R_(t)=1.33 min.

(b) 1-(4,5-Diamino-2-chloro-phenyl)-pyrrolidine-3-carbonitrile

Tin dichloride dihydrate (410 mg, 1.8 mmol) was added to1-(5-amino-2-chloro-4-nitro-phenyl)-pyrrolidine-3-carbonitrile (100 mg,0.4 mmol) in EtOAc (5 mL). The reaction mixture was stirred at refluxfor 1.5 h, cooled, diluted with EtOAc and water and basified with conc.ammonia. The mixture was filtered through a pad of celite. The organiclayer was dried over Na₂SO₄ and concentrated to give the sub-titlecompound.

Yield: 75 mg (42%). R_(f)(TLC): 0.40 (silica gel, DCM:EtOH:NH₄OH90:10:1). MS m/z: 283 [M+H]⁺. HPLC-method F: R_(t)=0.84 min.

(c)N-{4-Chloro-3-[5-chloro-6-(3-cyano-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}2,2-dimethyl-propionamide

The title compound was prepared fromN-(4-chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide (66 mg,0.2 mmol), 1-(4,5-diamino-2-chloro-phenyl)-pyrrolidine-3-carbonitrile(55 mg, 0.2 mmol) in DMF (2 mL) and DIC (39 μL, 0.2 mmol) in analogy toexample 6 step (c).

Yield: 50 mg (44%). R_(f)(TLC): 0.35 (silica gel, DCM:EtOH 95:5). MSm/z: 485 [M+H]⁺. HPLC-method G: R_(t)=1.22 min.

Example 9(R)—N-{4-Chloro-3-[5-chloro-6-(2-hydroxymethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanecarboxamide

(a)N-(4-Chloro-3-nitro-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide

TBTU (0.44 g, 1.4 mmol) and TEA (0.43 mL, 3.1 mmol) were added to1-trifluoromethyl-cyclopropanecarboxylic acid (0.19 g, 1.2 mmol) in THF(5 mL). After 10 min at rt 4-chloro-3-nitro-benzylamine (0.23 g, 1.2mmol) was added to the reaction mixture and stirring was continuedovernight. The mixture was concentrated, diluted with EtOAc and washedwith sat.aq. NaHCO₃-solution, water and brine. The organic layer wasdried over Na₂SO₄ and concentrated to give the subtitle compound.

Yield: 340 mg (86%). MS m/z: 321 [M+H]⁺. HPLC-method I: R_(f)=2.76 min.

(b)N-(4-Chloro-3-amino-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide

A mixture ofN-(4-chloro-3-nitro-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide(340 mg, 1.1 mmol), EtOAc (10 mL) and Ra—Ni (30 mg) was stirred at rtunder a hydrogen atmosphere (3 bar). The catalyst was removed byfiltration and the filtrate was concentrated to give the sub-titlecompound.

Yield: 250 mg (81%). R_(f)(TLC): 0.50 (silica gel, DCM:EtOH 95:5).HPLC-method G: R_(f)=1.30 min. MS m/z: 293 [M+H]⁺.

(c)N-(4-Chloro-3-isothiocyanato-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide

A mixture ofN-(4-chloro-3-amino-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide(100 mg, 0.3 mmol), N,N-diisopropylcarbodiimide (87 mg, 0.4 mmol) andDCM (5 mL) was strirred at rt overnight. The reaction mixture wasfiltered through a pad of silica gel and the filtrate was concentratedto give the sub-title compound.

Yield: 95 mg (83%). R_(f)(TLC): 0.75 (silica gel, CH:EtOAc 1:1). MS m/z:335 [M+H]⁺.

(d) (R)-1-(5-Amino-2-chloro-4-nitro-phenyl)-2-hydroxymethyl-pyrrolidine

(R)-2-Hydroxymethyl-pyrrolidine (202 mg, 2.0 mmol) followed by potassiumcarbonate (304 mg, 2.2 mmol) were added to a mixture of4,5-dichloro-2-nitro-phenylamine (414 mg, 2.0 mmol) in DMF (10 mL) andstirred at rt overnight. The reaction mixture was diluted with water,acidified with TFA:H₂O 1:1 and filtered. The filtercake was washed withDMF:H₂O 1:1 and dried to give the sub-title compound.

Yield: 220 mg (41%). HPLC-method J: R_(t)=1.91 min. MS m/z: 272 [M+H]⁺.

(e) (R)-1-(4,5-Diamino-2-chloro-phenyl)-2-hydroxymethyl-pyrrolidine

The sub-title compound was prepared from(R)-1-(5-amino-2-chloro-4-nitro-phenyl)-2-hydroxymethyl-pyrrolidine (220mg, 0.8 mmol) and Pt/C (50 mg) in MeOH (6 mL) and THF (6 mL) in analogyto example 1 step (f).

Yield: 186 mg (95%). HPLC-method C: R_(t)=1.22 min. MS m/z: 242 [M+H]⁺.

(f)(R)—N-{4-Chloro-3-[5-chloro-6-(2-hydroxymethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanecarboxamide

The title compound was prepared fromN-(4-chloro-3-isothiocyanato-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide(85 mg, 0.3 mmol),(R)-1-(4,5-diamino-2-chloro-phenyl)-2-hydroxymethyl-pyrrolidine (62 mg,0.3 mmol) and EDC (45 μL, 0.3 mmol) in MeCN (5 mL) in analogy with themethod described in example 1 step (g).

Yield: 3 mg (2%). HPLC-method J: R_(t)=1.56 min. MS m/z: 542 [M+H]⁺.

Example 10N-{4-Chloro-3-[5-chloro-1-methyl-6-morpholin-4-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanecarboxamide

(a) (4-Chloro-5-morpholin-4-yl-2-nitro-N-methyl-aniline

Morpholine (174 mg, 2.0 mmol) followed by potassium carbonate (304 mg,2.2 mmol) were added to a mixture of4,5-dichloro-N-methyl-2-nitroaniline (442 mg, 2.0 mmol) in DMF (10 mL)and stirred at rt overnight. The reaction mixture was acidified withTFA:H₂O 1:1 and purified by chromatography to give the sub-titlecompound.

Yield: 260 mg (48%). HPLC-method J: R_(t)=2.18 min. MS m/z: 272 [M+H]⁺.

(b) 5-Chloro-2-methylamino-4-morpholin-4-yl-aniline

The sub-title compound was prepared from(4-chloro-5-morpholin-4-yl-2-nitro-N-methyl-aniline (260 mg, 1.0 mmol),THF (6 mL), MeOH (6 mL) and Pt/C (50 mg) in analogy to example 1 step(f).

Yield: 219 mg (95%). HPLC-method C: R_(t)=1.57 min. MS m/z: 242 [M+H]⁺.

(c)N-{4-Chloro-3-[5-chloro-1-methyl-6-morpholin-4-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanecarboxamide

The title compound was prepared fromN-(4-chloro-3-isothiocyanato-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide(111 mg, 0.3 mmol), 5-chloro-2-methylamino-4-morpholin-4-yl-aniline (80mg, 0.3 mmol) and EDC (59 μL, 0.3 mmol) in MeCN (5 mL) in analogy withmethod described in example 1 step (g).

Yield: 53 mg (30%). HPLC-method J: R_(t)=1.68 min. MS m/z: 542 [M+H]⁺.

Example 11N-{4-Chloro-3-[5-chloro-1-methyl-6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanecarboxamide

(a) 4-Chloro-5-(4-methyl-piperazin-1-yl)-2-nitro-N-methyl-aniline

The sub-title compound was prepared from N-methylpiperazine (200 mg, 2.0mmol), 4,5-dichloro-N-methyl-2-nitroaniline (442 mg, 2.0 mmol) andpotassium carbonate (304 mg, 2.2 mmol) in DMF (10 mL) in accordance toexample 9 step (d).

Yield: 500 mg (88%). HPLC-method J: R_(t)=1.37 min. MS m/z: 285 [M+H]⁺.

(b) 5-Chloro-2-methylamino-4-(4-methyl-piperazin-1-yl)-aniline

The sub-title compound was prepared from4-chloro-5-(4-methyl-piperazin-1-yl)-2-nitro-N-methyl-aniline (500 mg,1.8 mmol), THF (6 mL), MeOH (6 mL) and Pt/C (50 mg) in analogy toexample 1 step (f).

Yield: 403 mg (90%). HPLC-method C: R_(t)=1.22 min. MS m/z: 255 [M+H]⁺.

(c)N-{4-Chloro-3-[5-chloro-1-methyl-6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanecarboxamide

The title compound was prepared fromN-(4-chloro-3-isothiocyanato-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide(176 mg, 0.5 mmol),5-chloro-2-methylamino-4-(4-methyl-piperazin-1-yl)-aniline (134 mg, 0.5mmol) and EDC (93 μL, 0.5 mmol) in MeCN (5 mL) in analogy to example 1step (g).

Yield: 84 mg. HPLC-method J: R_(t)=1.40 min. MS m/z: 555 [M+H]⁺.

Example 12N-{4-Chloro-3-[3-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

(a) N-Methyl-2-nitro-4-(4-trifluoromethyl-piperidin-1-yl)-aniline

Under argon sodium tert-butoxide (366 mg, 3.8 mmol) followed bypalladium(II) acetate (22 mg, 0.1 mmol) and tri-tert-butylphosphine 10%in toluene (450 μL, 0.2 mmol) were added to a mixture of4-bromo-2-nitro-N-methyl-aniline (440 mg, 1.9 mmol) and4-(trifluoromethyl)piperidine (660 mg, 2.9 mmol) in toluene (7 mL). Thereaction mixture was stirred at 100° C. overnight then allowed to cooland was concentrated. The crude was purified by chromatography to givethe sub-title compound.

Yield: 220 mg (38%). R_(f)(TLC): 0.56 (silica gel, DCM:EtOH 98:2). MSm/z: 304 [M+H]⁺.

(b) 2-Methylamino-5-(4-trifluoromethyl-piperidin-1-yl)aniline

A mixture ofN-methyl-2-nitro-4-(4-trifluoromethyl-piperidin-1-yl)-aniline (220 mg,0.7 mmol), MeOH (7 mL) and Pd/C (30 mg) was stirred for 18 h at rt undera hydrogen atmosphere (3.0 bar). The catalyst was removed by filtration,the filtrate was concentrated and directly used in the next step.

(c)N-(4-Chloro-3-{3-[2-methylamino-5-(4-trifluoromethyl-piperidin-1-yl)-phenyl]-thioureido}-benzyl)-2,2-dimethyl-propionamide

A mixture of 2-methylamino-5-(4-trifluoromethyl-piperidin-1-yl)aniline(90 mg, 0.3 mmol) andN-(4-chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide (93 mg,0.3 mmol) in THF (10 mL) was stirred at rt for 4 h. The reaction mixturewas concentrated and directly used in the next step. Yield: 180 mg(98%). HPLC-method A: R_(t)=2.23 min. MS m/z: 556 [M+H]⁺.

(d)N-{4-Chloro-3-[3-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

DIC (130 μL, 0.8 mmol) was added toN-(4-chloro-3-{3-[2-methylamino-5-(4-trifluoromethyl-piperidin-1-yl)-phenyl]-thioureido}-benzyl)-2,2-dimethyl-propionamide(180 mg, 0.3 mmol) in MeCN. The reaction mixture was heated at 60°C.-80° C. for one week (additional DIC (2.5 ml) was added). The mixturewas cooled to rt and concentrated. The residue was treated with MeCN,filtered and washed. The filtercake was diluted with dioxane and HCOOHand lyophilized to give the title compound.

Yield: 33 mg (20%). R_(f)(TLC): 0.65 (silica gel, DCM:EtOH 9:1). MS m/z:522 [M+H]⁺.

Example 23N-{2,4-Dichloro-3-[5-chloro-1-methyl-6-(3-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclobutaneamide

(a) (3-Amino-2,4-dichloro-benzyl)-carbamic acid tert-butyl ester

Boc₂O (1.48 g, 6.68 mmol) in 3.3 mL DCM was added at 0° C. to a mixtureof 3-amino-2,4-dichloro-benzylamine (1.16 g, 6.07 mmol), 6.7 mL DCM and12.1 mL 1 N NaOH-solution. The mixture was stirred vigourously for 2dand diluted with 5% aq NH₃-solution. The organic phase was separated andthe aq. phase was washed 2× with DCM. The combined organic phase waswashed with brine, dried with Na₂SO₄, filtered and concentrated to givethe sub-title compound.

Yield: 1.71 g (97%). R_(f)=0.65 (silica gel, DCM:EtOH 95:5). MS m/z: 291[M+H]⁺.

b) (2,4-Dichloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester

1,1′-Thiocarbonyldi-2-pyridone (0.42 g, 1.8 mmol) was added to a mixtureof (3-amino-2,4-dichloro-benzyl)-carbamic acid tert-butyl ester (0.50 g,1.7 mmol) and dioxane (25 mL) and stirred at rt for 2 h and at refluxfor 2 d. The mixture was concentrated, diluted with DCM and filteredover silica gel. The filtrate was concentrated to give the sub-titlecompound.

Yield: 0.49 g (86%). R_(f)=0.83 (silica gel, DCM:EtOH 95:5).

(c)N-{2,4-Dichloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzimidazol-2-ylamino]benzyl}-carbamicacid tert-butyl ester

The title compound was prepared from(2,4-dichloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester(5.47 g, 16.4 mmol),5-chloro-2-methylamino-4-(3-(trifluoromethyl)piperidin-1-yl)aniline(5.05 g, 16.4 mmol) and DIC 4.48 ml, 29 mmol) in MeCN in analogy toexample 6 step (c).

HPLC-method A: R_(t)=2.37 min. MS m/z: 606 [M+H]⁺.

(d)2,4-Dichloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzimidazol-2-ylamino]benzylamine

4 M HCl in dioxane (38 mL) was added toN-{2,4-dichloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzimidazol-2-ylamino]benzyl}-carbamicacid tert-butyl ester (5.4 g, 8.9 mmol) in dioxane (300 mL) and stirredat rt overnight. The reaction mixture was concentrated and the resultingresidue was diluted with aq. NaHCO₃-solution. The aq. phase wasextracted with EtOAc, the organic phase was dried with Na₂SO₄ andconcentrated.

Yield: 3.65 g (81%). HPLC-method A: R_(t)=1.33 min. MS m/z: 506 [M+H]⁺.

(e)N-{2,4-Dichloro-3-[5-chloro-1-methyl-6-(3-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclobutanecarboxamide

The title compound was prepared from TBTU (35 mg, 0.11 mmol), TEA (50μL, 0.36 mmol), 1-trifluormethyl-cyclobutanecarboxylic acid (57 mg, 0.4mmol) and2,4-dichloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzimidazol-2-ylamino]benzylamine(45.3 mg, 0.1 mmol) in DMF (3 mL) analogy to example 1 step (i).

Yield: 36 mg (55%). HPLC-method Q: R_(t)=1.73 min. MS m/z: 656 [M+H]⁺.

Example 30N-{4-Chloro-3-[5-(pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}cyclopropylsulfonamide

A TEA solution (0.35 M in DMF, 0.1 mL) was added to a4-Chloro-3-[5-(pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylaminesolution (0.12 M in MeCN, 0.1 mL, prepared in analogy to example 4d)followed by a cyclopropylsulfonyl chloride solution (0.12 M in MeCN, 0.1mL). The mixture was stirred overnight and filtered through basicalumina. The solids were washed with DMF/MeOH 9:1 and the combinedfiltrates were concentrated to give the title compound.

MS m/z: 446 [M+H]⁺. HPLC-method L: R_(t)=1.46 min.

Example 33N-{2-Fluoro-4-chloro-3-[5-chloro-1-methyl-6-(4-fluoro-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

(a) N-(6-Chloro-2-fluoro-3-methyl-phenyl)-acetamide

Acetylchloride (2.56 mL, 36.0 mmol) was added to a mixture of6-chloro-2-fluoro-3-methyl-aniline (5.00 g, 31.3 mmol) and toluene (200mL), additional toluene (50 mL) was added and the mixture was heated toreflux for 3 h. The reaction mixture was cooled with an ice bath and theformed precipitate was filtered off, washed with cold toluene and dried.

Yield: 4.75 g (75%). HPLC-method B: R_(t)=1.12 min. MS m/z: 202 [M+H]⁺.

(b) 3-Acetylamino-4-chloro-2-fluoro-benzoic acid

The sub-title compound was prepared fromN-(6-chloro-2-fluoro-3-methyl-phenyl)-acetamide and KMnO₄ in pyridine inanalogy to step 5a.

Yield: 49%. R_(t)=0.2 (silica gel, DCM/EtOH 4:1). HPLC R_(t)=0.93 min(method B). MS m/z: 232 [M+H]⁺.

(c) 3-Amino-4-chloro-2-fluoro-benzoic acid

The sub-title compound was prepared from3-acetylamino-4-chloro-2-fluoro-benzoic acid and 6 M HCl-solution inanalogy to step 5b.

Yield: 96%. HPLC R_(t)=1.10 min (method B). MS m/z: 190 [m+Fi]+

(d) 3-Amino-4-chloro-2-fluoro-benzamide

The sub-title compound was prepared from3-amino-4-chloro-2-fluoro-benzoic acid,(1-chloro-2-methyl-propenyl)-dimethyl-amine and conc. NH₃ in analogy tostep 5c.

Yield: 69%. R_(f)=0.3 (silica gel, PE:EtOAc 4:6). HPLC-method B:R_(t)=0.97 min. MS m/z: 189 [M+H]⁺.

(e) 3-Amino-4-chloro-2-fluoro-benzylamine

The crude sub-title compound was prepared from3-amino-4-chloro-2-fluoro-benzamide and LiAlH₄ in analogy to step 5d.

HPLC-method B: R_(t)=0.37 min. MS m/z: 175 [M+H]⁺.

(f) N-(3-Amino-4-chloro-2-fluoro-benzyl)-2,2-dimethyl-propionamide

The sub-title compound is prepared from crude3-amino-4-chloro-2-fluoro-benzylamine, 2,2-dimethyl-propionic acidchloride and TEA in analogy to example 5e.

Yield: 36% (side product in 29%:N-(3-Amino-4-chloro-benzyl)-2,2-dimethyl-propionamide).

R_(f)=0.6 (silica gel, PE:EtOAc 6:4). HPLC-method B: R_(t)=1.27 min. MSm/z: 259 [M+H]⁺.

(g)N-(4-Chloro-2-fluoro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide

The title compound is prepared fromN-(3-amino-4-chloro-2-fluoro-benzyl)-2,2-dimethyl-propionamide,1,1′-thiocarbonyldi-2-pyridone in analogy to step 5f.

(h)N-{2-Fluoro-4-chloro-3-[5-chloro-1-methyl-6-(4-fluoro-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

The title compound is prepared fromN-(4-chloro-2-fluoro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamideand 5-chloro-2-methylamino-4-(4-fluoropiperidin-1-yl)-aniline and DIC inanalogy to example 51.

Yield: 49%. R_(f)=0.5 (silica gel, PE:EtOAc 1:1). HPLC-method G:R_(t)=1.40 min. MS m/z: 524 [M+H]⁺.

Example 40N-{2,4-Dichloro-3-[5-chloro-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

(a) 4-Chloro-2-nitro-5-(4-trifluoromethyl-piperidin-1-yl)aniline

The sub-title compound was prepared from 4,5-dichloro-2-nitro-aniline(500 mg, 2.4 mmol), 4-trifluoromethyl-piperidine hydrochloride (550 mg,2.9 mmol) and K₂CO₃ (830 mg, 6.0 mmol) in DMSO (10 mL) in analogy toexample 3, step (a).

MS m/z: 324 [M+H]⁺. HPLC-method G: R_(t)=1.59 min

(b) 4-Chloro-2-amino-5-(4-trifluoromethyl-piperidin-1-yl)aniline

A mixture of4-chloro-2-nitro-5-(4-trifluoromethyl-piperidin-1-yl)aniline (0.63 g,1.9 mmol), THF (10 mL), MeOH (20 mL) and 50%-Pt-on-carbon (60 mg) wasstirred for 22 h at rt under a hydrogen atmosphere (3 bar). The catalystwas removed by filtration and the mixture was concentrated to give thesub-title compound.

HPLC-method G: R_(t)=1.22 min. MS m/z: 294 [M+H]⁺.

(c)N-{2,4-Dichloro-3-[5-chloro-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

The title compound was prepared fromN-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (108mg, 0.34 mmol),4-chloro-2-amino-5-(4-trifluoromethyl-piperidin-1-yl)aniline (100 mg,0.34 mmol), DIC (56 μL) in DMF (2 mL) in analogy to example 5, step (i).R_(f)(TLC): 0.35 (silica gel, DCM:EtOH 95:5). MS m/z: 576 [M+H]⁺.HPLC-method G: R_(f)=1.48 min.

Example 61N-{2,4-Dichloro-3-[5-trifluoromethyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]benzyl}-2,2-dimethyl-propionamide

(a)4-Trifluoromethyl-2-nitro-5-(4-trifluoromethyl-piperidin-1-yl)aniline

The sub-title compound was prepared from4-trifluoromethyl-5-chloro-2-nitro-aniline (100 mg, 0.42 mmol),4-trifluoromethyl-piperidine hydrochloride (394 mg, 2.1 mmol) and K₂CO₃(600 mg, 4.4 mmol) in NMP (2 mL) in analogy to example 3, step (a).

MS m/z: 356 [M+H]⁺. R_(f)(TLC): 0.8 (silica gel, DCM). HPLC-method G:R_(f)=1.62 min

(b)4-Trifluoromethyl-2-amino-5-(4-trifluoromethyl-piperidin-1-yl)aniline

A mixture of4-trifluoromethyl-2-nitro-5-(4-trifluoromethyl-piperidin-1-yl)aniline(0.14 g, 0.39 mmol), THF (10 mL) and Pd/C (15 mg) was stirred for 2 d atrt under a hydrogen atmosphere (3 bar). The catalyst was filtered offand the mixture was concentrated.

MS m/z: 328 [M+H]⁺. R_(f)(TLC): 0.2 (silica gel, DCM). HPLC-method G:R_(t)=1.42 min.

(c)N-{2,4-Dichloro-3-[5-trifluoromethyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

The compound was prepared fromN-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (87mg, 0.28 mmol),4-trifluoromethyl-2-amino-5-(4-trifluoromethyl-piperidin-1-yl)aniline(90 mg, 0.28 mmol), DIC (43 μL) in DMF (2 mL) in analogy to example 5,step (i).

Yield: 24%. R_(f)(TLC): 0.30 (silica gel, DCM:EtOH 95:5). MS m/z: 610[M+H]⁺. HPLC-method G: R_(t)=1.52 min.

Example 70N-{2,4-Difluoro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

(a) 3-Amino-2,4-difluoro-benzylamine

A mixture of 3-Nitro-2,4-difluoro-benzonitrile (0.50 g, 2.7 mmol), MeOH(25 ml), 37% HCl (1.5 ml) and Pd/C (200 mg) was stirred for 13 h at rtunder a hydrogen atmosphere (3 bar). The catalyst was removed byfiltration and the filtrate was concentrated.

Yield: 0.58 g. MS m/z: 159 [M+H]⁺.

(b) N-(3-Amino-2,4-difluoro-benzyl)-2,2-dimethyl-propionamide

TEA (1.92 mL, 13.8 mmol) was added to a mixture of3-amino-2,4-difluoro-benzylamine (0.58 g, 2.5 mmol) in THF (40 ml)followed by pivaloyl chloride (0.31 mL, 2.5 mmol) and it was stirredovernight. The mixture was diluted with EtOAc, washed successively withsatd. NaHCO₃ and brine. The organic phase was dried with Na₂SO₄,filtered and concentrated.

Yield: 0.57 g. HPLC-method G: R_(t)=1.20 min. MS m/z: 243 [M+H]⁺.

(c) N-(2,4-Difluoro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide

1,1′-Thiocarbonyldi-2-pyridone (546 mg, 2.35 mmol) was added to amixture of N-(3-amino-2,4-difluoro-benzyl)-2,2-dimethyl-propionamide(570 mg, 2.35 mmol) and dioxane (20 mL) and stirred at reflux overnight.The mixture was concentrated, diluted with DCM and filtered over silicagel. The filtrate was concentrated to give the sub-title compound.

Yield: 440 mg R_(f)(TLC): 0.8 (silica gel, DCM:EtOH 95:5).

(d)N-{2,4-Difluoro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-dimethyl-propionamide

The compound was prepared in analogy to example 5 (i) fromN-(2,4-difluoro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (68mg, 0.24 mmol),5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (100mg, 0.24 mmol), DIC (40 μL, 0.25 mmol) in DMF.

Yield: 50 mg (37%). R_(f)(TLC): 0.4 (silica gel, DCM:EtOH 95:5). MS m/z:558 [M+H]⁺. HPLC-method G: R_(t)=1.47 min.

Example 71N-{4-Chloro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]benzyl}-1-trifluoromethyl-cyclopropaneamide

A mixture ofN-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (0.15 g; 0.45 mmol) and5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (0.14g; 0.45 mmol) in DMF (3 mL) was stirred overnight at rt. EDC (0.086 g;0.45 mmol) was added and the mixture was heated to 90° C. for 1 h. Themixture was poured in water, extracted with DCM and the combined organiclayer was washed with brine, dried over Na₂SO₄, filtered, concentratedand purified by column chromatography.

Yield: 0.079 g (29%). HPLC-method N: R_(f)=13.92 min. MS m/z: 608[M+H]⁺.

Example 76N-{4-Chloro-3-[5-chloro-1-methyl-6-(4-phenyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

A mixture ofN-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (200 mg; 0.60 mmol) and5-chloro-2-methylamino-4-(4-phenyl-piperidin-1-yl)aniline (190 mg; 0.60mmol) in DMF (4 mL) was stirred overnight at rt. DIC (76 mg; 0.60 mmol)was added and the mixture was heated at 90° C. for 1.5 h. The mixturewas poured in water, extracted with EtOAc and the combined organic layerwas dried over Na₂SO₄, filtered and concentrated and the residue waspurified by column chromatography.

Yield: 69 mg (19%). HPLC-method O: R_(t)=11.40 min. MS m/z: 616 [M+H]⁺.

Example 82N-{4-Chloro-3-[5-cyano-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

(a) 2-Chloro-4-fluoro-5-nitrobenzonitrile

Fuming HNO₃ (2.9 mL, 64 mmol) was added dropwise to a solution of2-chloro-4-fluorobenzonitrile (5.0 g, 32 mmol) in conc. H₂SO₄ (5 mL) at0° C. The mixture was stirred at 0° C. for 15 min and at rt for 30 minwhereafter it was poured into ice. The precipitate was filtered off,washed with water and dried under vacuum.

Yield: 6.08 g (95%).

(b) 2-Chloro-4-(methylamino)-5-nitrobenzonitrile

A solution of MeNH₂ in THF (14.9 mL, 2 M, 29.8 mmol) was added dropwiseto a solution of 2-chloro-4-fluoro-5-nitrobenzonitrile (3.0 g, 15 mmol)in THF (100 mL) at −20° C. The mixture was stirred at −20° C. for 1 hand thereafter concentrated, washed with brine and extracted with EtOAc.The organic layer was dried over Na₂SO₄, filtered and concentrated. Theresulting residue was washed with PE to give the sub-title compound.

Yield: 3.07 g (97%).

(c)4-(Methylamino)-5-nitro-2-(4-trifluoromethyl-piperidin-1-yl)benzonitrile

A mixture of 2-chloro-4-(methylamino)-5-nitrobenzonitrile (3.07 g, 14.5mmol), 4-trifluoromethylpiperidine (3.33 g, 21.7 mmol), K₂CO₃ (5.01 g,36.2 mmol) and DMF (16 mL) was heated at 60° C. for 6 h under Aratmosphere. The mixture was poured into aqueous NH₄OH and extracted withEtOAc. The organic layer was dried over Na₂SO₄, filtered andconcentrated. Crystallization from EtOAc/PE gave the sub-title compound.

Yield: 3.65 g (77%).

(d)5-Amino-4-(methylamino)-2-(4-trifluoromethyl-piperidin-1-yl)benzonitrile

H₂ (1 atm) was passed through a mixture of4-(methylamino)-5-nitro-2-(4-trifluoromethyl-piperidin-1-yl)benzonitrile(204 mg, 0.62 mmol), Pd/C (66 mg, 0.062 mmol), EtOAc (10 mL) and EtOH(10 mL) at rt for 1 h. The mixture was filtered through celite andconcentrated. Crystallization from Et₂O/PE gave the sub-title compound.

Yield: 182 mg (98%).

(e)N-{4-Chloro-3-[5-cyano-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino}-benzyl]-1-trifluoromethyl-cyclopropanamide

The title compound was prepared in analogy to Example 76 using5-amino-4-(methylamino)-2-(4-trifluoromethyl-piperidin-1-yl)benzonitrile(179 mg, 0.60 mmol),N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (200 mg; 0.60 mmol), DIC (76 mg, 0.60 mmol) and DMF (4 mL).

Yield: 142 mg (40%). HPLC-method O: R_(t)=11.23 min. MS m/z: 599 [M+H]⁺.

Example 83N-{4-Chloro-3-[5-chloro-1-methyl-6-(4-(4-trifluoromethylphenyl)-piperazin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

(a)5-Chloro-2-methylamino-4-(4-(4-trifluoromethylphenyl)piperazin-1-yl)aniline

A mixture of4-chloro-N-methyl-2-nitro-5-(4-(4-trifluoromethylphenyl)-piperazin-1-yl)aniline(200 mg, 0.48 mmol), Ra—Ni (20 mg; 0.34 mmol) and THF (8 mL) was shakenunder H₂ atmosphere (1 atm) at rt for 4 h. The mixture was filteredthrough celite and the resulting solution was used immediately used inthe next step.

(b)N-{4-Chloro-3-[5-chloro-1-methyl-6-(4-(4-trifluoromethylphenyl)piperazin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

N-(4-Chloro-3-isothiocyanatobenzyl)-1-trifluoromethyl-cyclopropanecarboxamide (161 mg, 0.48 mmol) was added to the THF solution from step(a) above and the mixture was concentrated. DMF (2 mL) was added to theresidue, the mixture was stirred at rt for 1 h and DIC (67 mg, 0.53mmol) was added. The mixture was stirred at rt overnight, anotherportion of DIC (17 mg, 0.13 mmol) was added and the mixture was stirredat rt overnight. The mixture was concentrated and the residue waspurified by column chromatography to give the title compound.

Yield: 91 mg (28%). HPLC-method O: R_(t)=12.37 min. MS m/z: 685 [M+H]⁺.

Example 84N-{4-Chloro-3-[5,7-difluoro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

(a) 2,3,4-Trifluoro-N-methyl-6-nitroaniline

A solution of MeNH₂ in THF (50.7 mL, 2 M, 101 mmol) was added dropwiseto a solution of 1,2,3,4-tetrafluoro-5-nitrobenzene (9.88 g, 50.7 mmol)in THF (200 mL) at −20° C. The mixture was stirred at −20° C. for 1.5 h,concentrated, washed with brine and extracted with EtOAc. The organiclayer was dried over Na₂SO₄, filtered and concentrated. Crystallizationfrom EtOAc/PE gave the sub-title compound. Yield: 8.5 g (81%).

(b)2,4-Difluoro-N-methyl-6-nitro-3-(4-trifluoromethyl-piperidin-1-yl)aniline

A mixture of 2,3,4-trifluoro-N-methyl-6-nitroaniline (1.5 g, 7.3 mmol),4-trifluoromethyl-piperidine hydrochloride (2.76 g, 14.6 mmol), K₂CO₃(2.01 g, 14.6 mmol) and DMF (10 mL) was stirred at rt overnight under Aratmosphere. The mixture was poured into aqueous ammonia and extractedwith EtOAc. The organic layer was dried over Na₂SO₄, filtered andconcentrated. Crystallization from EtOAc/PE gave the sub-title compound.

Yield: 2.3 g (93%).

(c)3,5-Difluoro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline

A mixture of2,4-difluoro-N-methyl-6-nitro-3-(4-trifluoromethyl-piperidin-1-yl)aniline(210 mg, 0.62 mmol), Ra—Ni (4 mg, 0.062 mmol) and THF (30 mL) was shakenunder H₂ atmosphere (1 atm) at rt for 1 h. The mixture was filteredthrough celite and the celite pad was further washed with THF. Theresulting solution was concentrated to give the sub-title compound.

Yield: 190 mg (99%).

(d)N-{4-Chloro-3-[5,7-difluoro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

The title compound was prepared in analogy to Example 76 using3,5-difluoro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline(186 mg, 0.60 mmol),N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (200 mg; 0.60 mmol), DIC (76 mg, 0.60 mmol) and DMF (3 mL).

Yield: 119 mg (33%). HPLC-method O: R_(t)=12.25 min. MS m/z: 610 [M+H]⁺.

Example 86N-{4-Chloro-3-[5-fluoro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

(a) 4,5-Difluoro-N-methyl-2-nitroaniline

A solution of MeNH₂ in THF (5.7 mL, 2 M, 11 mmol) was added dropwise toa solution of 1,2,4-trifluoro-5-nitrobenzene (1.0 g, 5.7 mmol) in THF(10 mL) at −20° C. The mixture was stirred at −20° C. for 1 h,concentrated, washed with brine and extracted with EtOAc. The organiclayer was dried over Na₂SO₄, filtered and concentrated. Crystallizationfrom EtOAc/PE gave the sub-title compound. Yield: 1.0 g (81%).

(b)4-Fluoro-N-methyl-2-nitro-5-(4-trifluoromethyl-piperidin-1-yl)aniline

A mixture of 4,5-difluoro-N-methyl-2-nitroaniline (1.0 g, 5.3 mmol),4-trifluoromethylpiperidine hydrochloride (2.02 g, 10.6 mmol), K₂CO₃(1.47 g, 10.6 mmol) and DMF (7 mL) was stirred at 40° C. overnight underAr atmosphere. The mixture was poured into aqueous ammonia and extractedwith EtOAc. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was washed with Et₂O/PE to give the sub-titlecompound.

Yield: 1.6 g (95%).

(c) 5-Fluoro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline

A mixture of4-fluoro-N-methyl-2-nitro-5-(4-trifluoromethyl-piperidin-1-yl)aniline(200 mg, 0.62 mmol), Ra—Ni (4 mg, 0.062 mmol) and THF (30 mL) was shakenunder H₂ atmosphere (1 atm) at rt for 1 h. The mixture was filteredthrough celite and the celite pad was further washed with THF.Concentration and crystallization from Et₂O/PE gave the sub-titlecompound.

Yield: 176 mg (97%).

(d)N-{4-Chloro-3-[5-fluoro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

The title compound was prepared in analogy to Example 76 using5-fluoro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (175mg, 0.60 mmol),N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (200 mg; 0.60 mmol), DIC (76 mg, 0.60 mmol) and DMF (3 mL).

Yield: 155 mg (44%). HPLC-method O: R_(t)=10.62 min. MS m/z: 592 [M+H]⁺.

Example 93N-{4-Chloro-3-[4-cyano-5-(3-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

(a) 2-Amino-6-fluoro-3-nitrobenzonitrile

A solution of NH₃ in EtOH (19 mL, 8.6 M, 160 mmol) was added dropwise toa solution of 2,6-difluoro-3-nitrobenzonitrile (10 g, 54 mmol) in THF(50 mL) at 0° C. under Ar and the resulting mixture was stirred at 0° C.for 1 h. The mixture was concentrated and the residue washed with brineand extracted with EtOAc. The organic layer was dried over Na₂SO₄,filtered and concentrated.

Yield: 9.59 g (98%).

(b) 2-Amino-3-nitro-6-(3-trifluoromethyl-piperidin-1-yl)benzonitrile

A mixture of 2-amino-6-fluoro-3-nitrobenzonitrile (3.1 g, 17 mmol),3-trifluoromethylpiperidine (2.5 g, 19 mmol), TEA (3.4 g, 34 mmol) andTHF (110 mL) was stirred under Ar at rt for 3 h. The mixture wasconcentrated and poured into H₂O and thereafter extracted with EtOAc.The organic layer was dried over Na₂SO₄, filtered and concentrated.Crystallization from EtOAc gave the sub-title compound.

Yield: 2.9 g (54%).

(c) 2,3-Diamino-6-(3-trifluoromethyl-piperidin-1-yl)benzonitrile

A mixture of2-amino-3-nitro-6-(3-trifluoromethyl-piperidin-1-yl)benzonitrile (200mg, 0.64 mmol), Fe (178 mg, 3.18 mmol), aqueous NH₄Cl (5 mL) and EtOH (5mL) was heated under Ar at 90° C. for 2 h. The mixture was thereafterbasicified to pH ˜9-10 and filtered through celite and the celite padwas washed with EtOH and EtOAc. The organic layer was concentrated andthe residue was extracted with EtOAc. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was washed with Et₂O togive the sub-title compound.

Yield: 153 mg (84%).

(d)N-{4-Chloro-3-[4-cyano-5-(3-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

The title compound was prepared in analogy to Example 71 using2,3-diamino-6-(3-trifluoromethyl-piperidin-1-yl)benzonitrile (115 mg,0.40 mmol),N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (135 mg; 0.40 mmol), EDC (77 mg, 0.40 mmol) and DMF (3 mL).

Yield: 69 mg (29%). HPLC-method N: R_(t)=15.50 min. MS m/z: 585 [M+H]⁺.

Example 94N-{4-Chloro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-difluoro-propionamide

(a) Tert-butylN-{4-chloro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzyl}-carbamate

The sub-title compound was prepared in analogy to Example 76 using5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (508mg, 1.65 mmol), tert-butyl 4-chloro-3-isothiocyanatobenzylcarbamate (493mg, 1.65 mmol), DIC (208 mg, 1.65 mmol) and

DMF (8 mL).

Yield: 701 mg (74%).

(b)4-Chloro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzylamine

A mixture of tert-butylN-{4-chloro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzyl}-carbamate(790 mg, 1.38 mmol), TFA (1.54 mL, 20.7 mmol) and DCM (30 mL) wasstirred at rt overnight. The mixture was cooled to 0° C., basicified topH ˜10 and extracted with DCM. The organic layer was dried over Na₂SO₄,filtered and concentrated and the residue was washed with Et₂O/PE.

(c)N-{4-Chloro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-2,2-difluoro-propionamide

A mixture of 2,2-difluoropropanoic acid (37 mg; 0.34 mmol), HBTU (129mg; 0.34 mmol) and TEA (69 mg; 0.68 mmol) in DMF (1.5 mL) was stirredfor 30 min at rt and added to a solution of4-chloro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzylamine(161 mg; 0.34 mmol) in DMF (1.5 mL). The resulting mixture was stirredovernight at rt, poured into brine and extracted with EtOAc. The organiclayer was dried over Na₂SO₄, filtered and concentrated and the residuewas purified by column chromatography.

Yield: 87 mg (45%). HPLC-method O: R_(t)=10.60 min. MS m/z: 564 [M+H]⁺.

Example 99N-(4-Chloro-3-(5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)benzyl)-2-methylpropane-2-sulfonamide

(a)N-(4-Chloro-3-(5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)benzyl)-2-methylpropane-2-sulfinamide

A solution of 2-methylpropane-2-sulfinic acid chloride (83 mg, 0.59mmol) in DCM (2 mL) was added dropwise to a solution of4-chloro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzylamine(265 mg, 0.56 mmol), TEA (113 mg, 1.12 mmol) and DCM (3 mL) at 0° C.under Ar. The mixture was stirred at rt overnight, poured into H₂O andextracted with DCM. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated. Crystallization from DCM/PE gave thesub-title compound.

Yield: 298 mg (92%).

(b)N-(4-Chloro-3-(5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)benzyl)-2-methylpropane-2-sulfonamide

A mixture ofN-(4-chloro-3-(5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)benzyl)-2-methylpropane-2-sulfinamide(298 mg, 0.52 mmol), m-chloroperoxybenzoic acid (127 mg, 0.74 mmol) andDCM (20 mL) was stirred at rt overnight. The mixture was basicified topH ˜8-9 and extracted with EtOAc. The organic layer was dried overNa₂SO₄, filtered and concentrated. Crystallization from DCM/Et₂O gavethe title compound.

Yield: 39 mg (13%). HPLC-method O: R_(t)=10.84 min. MS m/z: 592 [M+H]⁺.

Example 101N-{4-Trifluoromethyl-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

(a) 3-Amino-4-trifluoromethyl-benzonitrile

A closed pressure tube charged with3-fluoro-4-trifluoromethyl-benzonitrile (10.0 g; 52.9 mmol) and liquidNH₃ (60 mL) was heated for 6 days at 90° C. The tube was cooled to −60°C. and opened. The mixture was allowed to stir for 1 h at rt, washedwith brine, extracted with EtOAc, dried over Na₂SO₄, filtered andconcentrated.

Yield: 10.2 g (quantitative; slightly contaminated).

(b) tert-Butyl 5-cyano-2-trifluoromethyl-phenylcarbamate

A mixture of 3-amino-4-trifluoromethyl-benzonitrile (10.0 g; 53.7 mmol),DCM (100 mL) and TEA (8.2 mL; 59 mmol) was treated dropwise with asolution of Boc₂O (12.9 g; 59.1 mmol) in DCM (50 mL) at 0° C. andstirred overnight. Another portion of Boc₂O in DCM and DMAP (656 mg;5.37 mmol) was added and the mixture was stirred for another 12 h at rt.The mixture was washed with water and brine, dried over Na₂SO₄,filtered, concentrated and purified by column chromatography.

Yield: 8.50 g (55%).

(c) tert-Butyl 5-aminomethyl-2-trifluoromethyl-phenylcarbamate

A mixture of tert-butyl 5-cyano-2-trifluoromethyl-phenylcarbamate (8.5g; 29.7 mmol), Ra—Ni (174 mg; 2.97 mmol) and THF (60 mL) was stirredunder H₂-atmosphere (5 atm) overnight at rt. The mixture was filteredthrough celite and the celite pad was washed with THF and EtOAc.Concentration gave the sub-title compound which was used in the nextstep without further purification. Yield: 8 g (93%).

(d)N-(3-Amino-4-trifluoromethyl-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide

The compound was prepared in analogy to the procedures in Example 94,step (c) and Example 94, step (b) using tert-butyl5-aminomethyl-2-trifluoromethyl-phenylcarbamate (2.09 g; 7.20 mmol),1-trifluoromethyl-cyclopropanecarboxylic acid (1.11 g; 7.20 mmol), HBTU(2.73 g; 7.20 mmol), TEA (2.19 g; 21.6 mmol), DMF (25 mL), TFA (10 mL)and DCM (50 mL). Yield: 1.8 g (77%).

(e)N-(4-Trifluoromethyl-3-isothiocyanatobenzyl)-1-trifluoromethyl-cyclopropanecarboxamide

A mixture ofN-(3-amino-4-trifluoromethyl-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide(1.60 g; 4.90 mmol), di-(2-pyridyl)thionocarbonate (1.71 g; 7.36 mmol)and THF (40 mL) was stirred in a pressure tube for 2 days at 60° C. Themixture was concentrated and the residue was purified by columnchromatography. Yield: 1.29 g (72%).

(f)N-{4-Trifluoromethyl-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

The title compound was prepared in analogy to Example 76 using5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (185mg, 0.60 mmol),N-(4-trifluoromethyl-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (221 mg, 0.60 mmol), DIC (76 mg, 0.60 mmol) and DMF (4 mL).

Yield: 185 mg (48%). HPLC-method O: R_(t)=11.17 min. MS m/z: 642 [M+H]⁺.

Example 105N-{4-Trifluoromethyl-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-3,3,3-trifluoro-2-methyl-propanamide

(a) 3-Isothiocyanato-4-trifluoromethyl-benzonitrile

A mixture of 3-amino-4-trifluoromethyl-benzonitrile (1.0 g, 5.4 mmol),di-(2-pyridyl)thionocarbonate (1.87 g, 8.06 mmol) and THF (50 mL) wasstirred at rt overnight. The mixture was concentrated and the residuewas purified by column chromatography.

Yield: 760 mg (62%).

(b)3-(5-Chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)-4-trifluoromethyl-benzonitrile

The sub-title compound was prepared in analogy to Example 76 using5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (998mg, 3.24 mmol), 3-isothiocyanato-4-(trifluoromethyl)benzonitrile (740mg, 3.24 mmol), DIC (409 mg, 3.24 mmol) and DMF (7 mL).

Yield: 1.21 g (74%).

(c)4-Trifluoromethyl-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine

A mixture of3-(5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)-4-trifluoromethyl-benzonitrile(1.20 g; 2.39 mmol), Ra—Ni (14 mg; 0.24 mmol) and THF (50 mL) was shakenunder H₂-atmosphere (5 atm) overnight at rt. The mixture was filteredthrough celite and the celite pad was washed with THF and EtOAc.Concentration and crystallization from Et₂O/PE gave the sub-titlecompound.

Yield: 1.2 g (99%).

(d)N-{4-Trifluoromethyl-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-3,3,3-trifluoro-2-methyl-propanamide

The title compound was prepared in analogy to the procedure in Example94, step (c) using4-trifluoromethyl-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine(110 mg; 0.22 mmol), 3,3,3-trifluoro-2-methylpropanoic acid (31 mg; 0.22mmol), HBTU (83 mg; 0.22 mmol), TEA (45 mg; 0.44 mmol), DMF (2 mL).

Yield: 39 mg (28%). HPLC-method O: R_(t)=11.80 min. MS m/z: 630 [M+H]⁺.

Example 109N-(4-Trifluoromethyl-3-(5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)benzyl)-2-methylpropane-2-sulfinamide

The title compound was prepared in analogy to the procedure in Example99, step (a) using 2-methylpropane-2-sulfinic chloride (117 mg, 0.83mmol),4-trifluoromethyl-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine(400 mg, 0.79 mmol), TEA (160 mg, 1.58 mmol) and DCM (5 mL).

Yield: 210 mg (44%). HPLC-method O: R_(t)=11.25 min. MS m/z: 610 [M+H]⁺.

Example 110N-(4-Trifluoromethyl-3-(5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)benzyl)-2-methylpropane-2-sulfonamide

A mixture ofN-(4-trifluoromethyl-3-(5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)benzyl)-2-methylpropane-2-sulfinamide(140 mg, 0.23 mmol), m-chloroperoxybenzoic acid (198 mg, 1.15 mmol) andCHCl₃ (7 mL) was stirred at rt for 15 min. The mixture was poured intobrine and extracted with DCM. The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was mixed with PBr₃ (144 mg, 0.50mmol) and DCM (5 ml) and the mixture was stirred at rt overnight. Themixture was poured into H₂O and extracted with DCM. The organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentrated.Purification by column chromatography gave the title compound.

Yield: 33 mg (16%). HPLC-method O: R_(t)=11.44 min. MS m/z: 626 [M+H]⁺.

Example 111N-{4-Fluoro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

(a) 4-Fluoro-3-nitro-benzylamine hydrochloride

BH₃/THF (120 mL; 120 mmol) was added to a solution of4-fluoro-3-nitro-benzonitrile (10 g; 60 mmol) in THF (50 mL) over 30 minat 0° C. and the resulting mixture was stirred at 0° C. for 1 h and atrt for 3 h. The mixture was acidified to pH ˜1 and stirred for 1 h atrt, basicified to pH ˜7-8 and extracted with EtOAc. The organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue wasdissolved in Et₂O and treated with a solution of HCl in 1,4-dioxane togive the sub-title compound.

Yield: 8.7 g (70%).

(b)N-(4-Fluoro-3-nitro-benzyl)-1-(trifluoromethyl)cyclopropanecarboxamide

The sub-title compound was prepared in analogy to the procedure inExample 94, step (c) using 4-fluoro-3-nitro-benzylamine hydrochloride(3.0 g; 14.5 mmol), 1-(trifluoromethyl)-cyclopropanecarboxylic acid (2.5g; 16.0 mmol), HBTU (6.07 g; 16.0 mmol), TEA (5.88 g; 58.1 mmol) and DMF(50 mL).

Yield: 3.8 g (85%).

(c)N-(3-Amino-4-fluorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide

The sub-title compound was prepared in analogy to the procedure inExample 93, step (c) usingN-(4-fluoro-3-nitrobenzyl)-1-(trifluoromethyl)-cyclopropanecarboxamide(3.77 g; 12.3 mmol), Fe (3.45 g; 61.6 mmol), NH₄Cl (aq, sat, 30 mL) andEtOH (30 mL).

Yield: 3.2 g (76%).

(d) N-(4-Fluoro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide

A mixture ofN-(3-amino-4-fluorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide(3.17 g; 11.5 mmol) and TCDI (3.07 g; 17.2 mmol) in DCM (50 mL) washeated overnight at 50° C. The mixture was concentrated and the residuewas purified by column chromatography.

Yield: 3 g (82%).

(e)N-{4-Fluoro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

The title compound was prepared in analogy to the procedure in Example76 usingN-(4-fluoro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (191 mg; 0.60 mmol),5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (185mg; 0.60 mmol), DIC (76 mg; 0.60 mmol) and DMF (3 mL).

Yield: 111 mg (31%). HPLC-method O: R_(t)=11.07 min. MS m/z: 592 [M+H]⁺.

Example 114N-{4-Chloro-2-fluoro-5-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

(a) 4-Chloro-2-fluoro-5-nitrobenzonitrile

A mixture of 4-chloro-2-fluorobenzonitrile (4.62 g; 29.7 mmol) in conc.H₂SO₄ (42 mL) was treated dropwise with conc. HNO₃ (3.9 mL) at 1-2° C.After stirring at 1-2° C. for 2 h the mixture was poured into ice andfiltered.

Yield: 5.18 g (87%).

(b) 4-Chloro-2-fluoro-5-isothiocyanatobenzonitrile

H₂ was passed through a mixture of 4-chloro-2-fluoro-5-nitrobenzonitrile(1.0 g; 5.0 mmol) and Ra—Ni (29 mg, 0.50 mmol) in THF (50 mL) for 6 h.The mixture was filtered through celite. CSCl₂ (2.29 g; 19.9 mmol) andK₂CO₃ (3.45 g; 25.0 mmol) was added and it was stirred overnight at rt.The residue was concentrated and purified by column chromatography.

Yield: 840 mg (79%).

(c)4-Chloro-5-[5-chloro-1-methyl-6-(4-(trifluoromethyl)piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]-2-fluorobenzonitrile

The sub-title compound was prepared in analogy to the procedure inExample 76 using 4-chloro-2-fluoro-5-isothiocyanatobenzonitrile (300 mg;1.41 mmol),5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (434mg; 1.41 mmol), DIC (178 mg; 1.41 mmol) and DMF (12 mL).

Yield: 264 mg (39%).

(d)4-Chloro-2-fluoro-5-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine

The sub-title compound was prepared in analogy to Example 101, step (c)using4-chloro-5-[5-chloro-1-methyl-6-(4-(trifluoromethyl)piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]-2-fluorobenzonitrile(264 mg; 0.54 mmol), Ra—Ni (3 mg), H₂ (5 atm) and THF (30 mL).

(e)N-{4-Chloro-2-fluoro-5-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

The title compound was prepared in analogy to the procedure in Example94, step (c) using4-chloro-2-fluoro-5-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine(270 mg; 0.55 mmol), 1-trifluoromethyl-cyclopropanecarboxylic acid (85mg; 0.55 mmol), HBTU (209 mg; 0.55 mmol), TEA (111 mg; 1.10 mmol) andDMF (5 mL)

Yield: 79 mg (23%). HPLC-method O: R_(t)=11.47 min. MS m/z: 626 [M+H]⁺.

Example 116N-{4-Chloro-5-fluoro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

(a) 3-Fluoro-4-hydroxy-5-nitro-benzonitrile

Fuming HNO₃ (1.8 mL; 44 mmol) was added dropwise to a solution of3-fluoro-4-hydroxybenzonitrile (4.0 g; 29 mmol) in conc. H₂SO₄ (10 mL)at −10° C. The mixture was stirred at −10° C. for 1 h and thereafterslowly poured into ice. The precipitate was filtered off and thefiltrate was extracted with EtOAc. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was combined with theprecipitate and crystallized from EtOAc/PE to give the sub-titlecompound.

Yield: 3.9 g (73%).

(b) 4-Chloro-3-fluoro-5-nitro-benzonitrile

Oxalyl chloride (5.44 g; 42.8 mmol) was added dropwise to a solution of3-fluoro-4-hydroxy-5-nitrobenzonitrile (3.9 g; 21 mmol) in DMF (40 mL)at −25° C. The mixture was stirred at −25° C. for 15 min and thereafterat 80° C. for 2.5 h. The mixture was slowly poured into ice, theprecipitate was filtered off and the filtrate was extracted with EtOAc.The organic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was combined with the precipitate and filtered through a plug ofsilica gel to give the sub-title compound.

Yield: 2.44 g (56%).

(c) 4-Chloro-3-fluoro-5-nitro-benzylamine

A solution of BH₃/THF (7.5 mL; 7.5 mmol) was added dropwise to asolution of 4-chloro-3-fluoro-5-nitrobenzonitrile (750 mg; 3.74 mmol) inTHF (5 mL) at 0° C. The mixture was stirred at 0° C. for 3 h, it wasacidified to pH ˜1 and stirred at rt for 1 h and then basicified to pH˜8 and extracted with EtOAc. The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was dissolved in Et₂O andprecipitated with PE to give the sub-title compound.

Yield: 761 mg (99%).

(d)N-(4-Chloro-3-fluoro-5-nitro-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide

The sub-title compound was prepared in analogy to the procedure inExample 94, step (c) using 4-chloro-3-fluoro-5-nitro-benzylamine (761mg; 3.72 mmol), 1-trifluoromethyl-cyclopropanecarboxylic acid (573 mg;3.72 mmol), HBTU (1.41 g; 3.72 mmol), TEA (753 mg; 7.44 mmol) and DMF(10 mL).

Yield: 980 mg (77%).

(e)N-(3-Amino-4-chloro-5-fluoro-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide

H₂ was passed through a shaken mixture ofN-(4-chloro-3-fluoro-5-nitrobenzyl)-1-trifluoromethyl-cyclopropanecarboxamide(980 mg, 2.88 mmol), Ra—Ni (17 mg, 0.29 mmol) and THF (50 mL) at rt for1.5 h. The mixture was filtered through celite and concentrated.

Yield: 800 mg (89%).

(f)N-(4-Chloro-5-fluoro-3-isothiocyanatobenzyl)-1-trifluoromethyl-cyclopropanecarboxamide

The sub-title compound was prepared in analogy to Example 105, step (a)usingN-(3-amino-4-chloro-5-fluorobenzyl)-1-trifluoromethyl-cyclopropanecarboxamide(800 mg, 2.57 mmol), di-(2-pyridyl)thionocarbonate (897 mg, 3.86 mmol)and THF (20 mL).

Yield: 211 mg (23%).

(g)N-{4-Chloro-5-fluoro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-1-trifluoromethyl-cyclopropanamide

The title compound was prepared in analogy to the procedure in Example76 usingN-(4-chloro-5-fluoro-3-isothiocyanatobenzyl)-1-trifluoromethyl-cyclopropanecarboxamide (211 mg; 0.60 mmol),5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (184mg; 0.60 mmol), DIC (78 mg; 0.60 mmol) and DMF (4 mL).

Yield: 75 mg (20%). HPLC-method O: R_(t)=11.80 min. MS m/z: 626 [M+H]⁺.

Example 117N-{3-(5-Cyano-6-[3-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]-4-trifluoromethoxy-benzyl}-2,2-dimethyl-propionamide

(a) N-(4-Trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide

A solution of pivaloyl chloride (2.1 mL, 17 mmol) in MeCN (10 mL) wasadded dropwise over 10 min to a solution of4-trifluoromethoxy-benzylamine (2.6 mL, 17 mmol) and TEA (4.0 mL, 29mmol) in MeCN (20 mL) at 0° C. The mixture was stirred for 30 min,filtered and concentrated. The residue was treated with water andfiltration gave the sub-title compound.

Yield: 4.12 g (88%).

(b) N-(3-Nitro-4-trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide

Nitronium tetrafluoroborate (3.97 g, 29.9 mmol) was added in portionsover 5 min to N-(4-trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide(4.1 g, 15 mmol) in MeNO₂ (35 mL) and the mixture was stirred at rt for1 h. The mixture was treated with ice and Et₂O was added. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue wastreated with PE and the sub-title compound was filtered off.

Yield: 3.40 g (71%).

(c) N-(3-Amino-4-trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide

A mixture ofN-(3-nitro-4-trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide (3.4 g,11 mmol), Fe (3.7 g, 66 mmol), saturated aqueous NH₄Cl-solution (35 mL)and EtOH (170 mL) was refluxed for 30 min. The mixture was concentrated,treated with water and the pH was adjusted to ˜8. The mixture wasextracted with EtOAc and the organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was treated with PE and thesub-title compound was filtered off. Yield: 2.7 g (88%).

(d)N-(3-Isothiocyanato-4-trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide

A mixture ofN-(3-amino-4-trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide (200 mg,0.69 mmol), TCDI (133 mg, 0.746 mmol) and MeCN (3 mL) was refluxed for 1h. Concentration and purification by column chromatography gave thesub-title compound.

Yield: 135 mg (59%).

N-{3-[5-Cyano-6-(3-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]-4-trifluoromethoxy-benzyl}-2,2-dimethyl-propionamide

A mixture ofN-(3-isothiocyanato-4-trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide(135 mg, 0.406 mmol),4,5-diamino-2-(3-trifluoromethyl-piperidin-1-yl)benzonitrile (115 mg,0.406 mmol) and DMF (2 mL) was stirred at rt for 4 h. EDC (101 mg, 0.527mmol) was added and mixture was stirred at rt overnight. The mixture wastreated with water and extracted with Et₂O. Concentration andpurification by column chromatography gave an oil. The oil was treatedwith CHCl₃ and the precipitate was collected by filtration.

Yield: 52 mg (22%). HPLC-method N: R_(t)=14.60 min. MS m/z: 583 [M+H]⁺.

Example 133

(S)—N-{4-Chloro-3-[5-chloro-6-(2-methoxymethyl-pyrrolidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzyl}-1-trifluoromethyl-cyclopropanecarboxamide

(a)(S)-5-Chloro-2-isothiocyanato-4-(2-(methoxymethyl)pyrrolidin-1-yl)-nitrobenzene

A mixture of(S)-4-chloro-5-(2-(methoxymethyl)pyrrolidin-1-yl)-2-nitroaniline (200mg; 0.70 mmol), NaHCO₃ (588 mg; 7.00 mmol), CH₂Cl₂ (7 mL) and SCCl₂ (402mg; 3.50 mmol) was stirred at rt overnight and concentrated and theresidue was purified by column chromatography. Yield: 170 mg (74%).

(b)(S)—N-(4-Chloro-3-(3-(4-chloro-5-(2-(methoxymethyl)pyrrolidin-1-yl)-2-nitrophenyl)thioureido)benzyl)-1-(trifluoromethyl)cyclopropanecarboxamide

A mixture ofN-(3-amino-4-chlorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide(150 mg; 0.51 mmol),(S)-5-chloro-2-isothiocyanato-4-(2-(methoxymethyl)pyrrolidin-1-yl)-nitrobenzene(169 mg; 0.51 mmol) and DMF (3 mL) was stirred at rt overnight. Themixture was poured into brine and extracted with CH₂Cl₂. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue waswashed with Et₂O to give the sub-title compound.

Yield: 145 mg (46%).

(c)(S)—N-(3-(3-(2-Amino-4-chloro-5-(2-(methoxymethyl)pyrrolidin-1-yl)phenyl)thioureido)-4-chlorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide

A mixture of(S)—N-(4-chloro-3-(3-(4-chloro-5-(2-(methoxymethyl)pyrrolidin-1-yl)-2-nitrophenyl)thioureido)benzyl)-1-(trifluoromethyl)cyclopropanecarboxamide(145 mg; 0.23 mmol), Fe (65 mg; 1.2 mmol), saturated aqueousNH₄Cl-solution (3 mL) and EtOH (3 mL) was stirred at 90° C. for 2 h. Themixture was basicified to pH-9-10 and filtered through celite. Thecelite pad was washed with EtOH and EtOAc. The mixture was concentratedand the residue was extracted with EtOAc. The organic layer was driedover Na₂SO₄, filtered and concentrated. The residue was washed with Et₂Oto give the sub-title compound.

Yield: 110 mg (81%).

(d)(S)—N-(4-Chloro-3-(5-chloro-6-(2-(methoxymethyl)pyrrolidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)benzyl)-1-(trifluoromethyl)cyclopropanecarboxamide

A mixture of(S)—N-(3-(3-(2-amino-4-chloro-5-(2-(methoxymethyl)pyrrolidin-1-yl)phenyl)thioureido)-4-chlorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide(110 mg; 0.19 mmol), EDC (36 mg; 0.19 mmol) and DMF (4 mL) was stirredat 90° C. overnight. The mixture was poured into brine and extractedwith CH₂Cl₂. The organic layer was dried over Na₂SO₄, filtered andconcentrated and the residue was purified by column chromatography.

Yield: 29 mg (27%). HPLC-method N: R_(t)=12.10 min. MS m/z: 556 [M+H]⁺.

The following examples were prepared in analogy to the indicated methodsdescribed above using the appropriate building blocks.

Pre- Rf pared (TLC) in or Rt anal- MS* [min] ogy m/z (HPLC- to [M +meth- exam- Ex. Structure Formula/Mw. H]⁺ od) ple 13

C₂₅H₂₅Cl₂F₆N₅O 596.39 596 Rt = 2.31 (method C) 12 14

C₂₅H₂₅Cl₂F₆N₅O₂ 612.39 612 Rt: 2.56 (method K) 12 15

C₂₄H₂₄Cl₂F₅N₅O 564.38 564 Rt: 2.78 (method D) 12 16

C₂₅H₃₂ClN₅O 454.02 454 Rt: 1.66 (method L) 1(i) 17

C₂₅H₂₅ClF₃N₅O 479.93 480 Rt: 1.62 (method L) 1(i) 18

C₂₅H₃₂ClN₅O 454.02 454 Rt: 1.69 (method L) 1(i) 19

C₂₆H₃₂ClN₅O 466.03 466 Rt: 1.67 (method L) 1(i) 20

C₂₃H₂₈ClN₅O 425.96 426 Rt: 1.51 (method L) 1(i) 21

C₃₂H₃₀ClN₅O₂ 552.08 552 Rt: 1.78 (method L) 1(i) 22

C₂₈H₂₅ClN₆O 497.00 497 Rt: 1.66 (method L) 1(i) 24

C₂₇H₂₇Cl₃F₃N₅O 600.9 600 Rt: 1.68 (method Q) 23 25

C₂₆H₂₂Cl₄F₃N₅OS 651.37 650 Rt: 1.77 (method Q) 23 26

C₂₃H₂₃ClN₆O 434.93 435 Rt: 1.46 (method L) 1(i) 27

C₂₆H₂₉ClF₃N₅O 520.00 520 Rt: 1.68 (method L) 1(i) 28

C₂₅H₃₀ClN₅O 452.00 452 Rt: 1.62 (method L) 1(i) 29

C₂₂H₂₂ClN₅O₃S 471.97 472 Rt: 1.54 (method L) 30 31

C₂₃H₂₈ClN₅O₂ 441.96 442 Rt: 1.40 (method L) 1(i) 32

C₂₄H₂₅ClN₆OS 481.02 481 Rt: 1.47 (method L) 1(i) 34

C₂₂H₂₂ClN₅O₃S 471.97 472 Rt: 1.53 (method L) 30 35

C₂₆H₃₀ClN₅O 464.01 464 Rt: 1.64 (method L) 1(i) 36

C₂₆H₃₃ClN₆O 481.04 480 Rt: 1.33 (method L) 1(i) 37

C₂₅H₃₂Cl₂FN₅O₂ 524.46 524 Rf : 0.3 (silica; DCM: EtOH 95:5) 33 38

C₂₅H₂₅ClN₆O 460.97 460 Rt: 1.31 (method L) 1(i) 39

C₂₃H₂₃ClN₆O₂ 450.93 451 Rt: 1.48 (method L) 1(i) 41

C₂₇H₂₈ClN₅O 474.01 474 Rt: 1.62 (method L) 1(i) 42

C₂₅H₃₀Cl₂FN₅O₂ 522.442 522 Rt: 1.20 (method G) 33 43

C₃₀H₂₇ClN₆O 523.04 523 Rt: 1.40 (method L) 1(i) 44

C₂₃H₂₂ClN₇O 447.93 448 Rt: 1.40 (method L) 1(i) 45

C₂₄H₂₅ClN₆O 448.96 449 Rt: 1.54 (method L) 1(i) 46

C₂₃H₂₄ClN₇O 449.94 448 Rt: 0.32 (method L) 1(i) 47

C₂₃H₂₃ClN₆O₂ 450.93 451 Rt: 0.60 (method L) 1(i) 48

C₂₄H₂₇Cl₂F₂N₅O 510.408 510 Rt: 1.41 (method G) 33 49

C₂₉H₂₆ClN₅O 496.01 496 R_(t): 1.74 (method L) 1(i) 50

C₂₇H₂₄ClN₅O 469.97 470 R_(t): 0.68 (method L) 1(i) 51

C₂₆H₂₉Cl₃F₃N₅O₂ 606.894 606 R_(t): 2.37 (method A)  1 52

C₂₅H₂₇Cl₃F₃N₅O 576.87 576  5 53

C₂₆H₂₉Cl₃F₃N₅O 590.90 590 R_(t): 1.51 (method G)  5 54

C₂₇H₂₃Cl₄F₃N₆O 646.33 645 R_(t): 1.52 (method M) 1(i) 55

C₂₄H₂₃Cl₂F₆N₅O₂ 598.37 596 R_(t): 1.43 (method M) 1(i) 56

C₂₆H₂₅Cl₃F₅N₅O 624.87 624 R_(t): 1.97 (method Q) 1(i) 57

C₂₆H₂₇Cl₂F₆N₅O₂ 626.43 626 R_(t): 1.93 (method L) 1(i) 58

C₃₂H₃₄Cl₂F₃N₅O 632.56 632 R_(t): 2.03 (method L) 1(i) 59

C₂₅H₂₇Cl₃F₃N₅O 576.87 576 R_(t): 1.50 (method G)  5 60

C₂₆H₂₂Cl₄F₃N₅OS 651.37 650 R_(t): 1.69 (method Q) 23 62

C₂₂H₂₂Cl₂F₃N₅O 500.34 500 R_(t): 1.54 (method J) 71 63

C₃₁H₃₀Cl₂F₃N₅O 616.51 616 R_(t): 2.00 (method L) 1(i) 64

C₃₁H₃₁Cl₃F₃N₅O 652.97 652 R_(t): 2.05 (method L) 1(i) 65

C₂₄H₂₄Cl₂F₆N₆O 597.39 597 R_(t): 1.69 (method L) 1(i) 66

C₂₆H₂₈Cl₂F₃N₅O₂ 570.44 570 R_(t): 1.81 (method L) 1(i) 67

C₃₁H₂₉Cl₂F₆N₅O₂ 688.50 688 R_(t): 2.04 (method L) 1(i) 68

C₂₈H₂₄Cl₄F₃N₅O 645.34 644 R_(t): 1.96 (method L) 1(i) 69

C₂₉H₂₄Cl₂F₇N₅O 662.44 662 R_(t): 1.96 (method L) 1(i) 72

C₂₅H₂₃Cl₂F₆N₅O 594.38 594 R_(t): 13.74 (method N) 71 73

C₂₆H₂₇Cl₂F₃N₆O₂ 583.43 583 R_(t): 11.03 (method N) 71 74

C₂₅H₂₅Cl₂F₃N₆O₂ 569.41 569 R_(t): 10.87 (method N) 71 75

C₂₅H₂₃Cl₂F₆N₅O 594.38 594 R_(t): 13.70 (method N) 71 77

C₂₆H₂₈Cl₂F₃N₅O₂ 570.43 570 R_(t): 9.55 (method O) 76 78

C₂₇H₃₀Cl₂F₃N₅O 568.46 568 Rt: 11.39 (method O) 76 79

C₂₅H₂₄Cl₂F₅N₅O 576.39 576 Rt: 10.59 (method O) 76 80

C₂₉H₃₂Cl₂F₆N₆O 665.50 665 Rt: 10.67 (method O) 76 81

C₂₆H₂₉Cl₂F₆N₅O₂ 652.46 652 Rt: 12.90 (method O) 76 85

C₂₇H₂₉ClF₅N₅O 570.00 570 Rt: 12.64 (method O) 84 87

C₂₇H₃₀ClF₄N₅O 552.01 552 Rt: 10.65 (method O) 86 88

C₂₉H₂₉Cl₂F₆N₅O 648.47 648 Rt: 11.70 (method O) 76 89

C₂₇H₂₄Cl₂F₉N₅O 676.40 676 Rt: 13.07 (method O) 76 90

C₃₀H₂₉Cl₂F₃N₆O 617.49 617 Rt: 11.23 (method O) 76 91

C₃₁H₂₉Cl₂F₄N₅O 634.49 634 Rt: 11.88 (method O) 76 92

C₂₆H₂₆Cl₂F₆N₆O 623.42 623 Rt: 10.85 (method O) 76 95

C₂₉H₂₉Cl₂F₂N₅O 572.48 572 Rt: 11.20 (method O) 94 96

C₂₉H₂₇Cl₂F₅N₆O 641.46 641 Rt: 12.00 (method O) 94 97

C₃₁H₃₂Cl₂F₃N₅O 618.52 618 Rt: 12.02 (method O) 94 98

C₃₁H₃₀Cl₂F₆N₆O 687.51 687 Rt: 12.19 (method O) 94 100

C₃₀H₃₃Cl₂F₃N₆O₂S 669.59 669 Rt: 12.12 (method O) 99 102

C₂₆H₂₆ClF₆N₅O 573.96 574 Rt: 10.53 (method O) 101  103

C₂₉H₂₄Cl₂F₇N₅O 662.43 662 Rt: 11.10 (method O) 101  104

C₂₇H₃₀ClF₆N₅O 590.00 590 Rt: 11.03 (method O) 101  106

C₂₅H₂₄ClF₈N₅O 597.93 598 Rt: 11.23 (method O) 105  107

C₂₆H₂₆ClF₆N₅O₂ 589.96 590 Rt: 10.50 (method O) 105  108

C₂₆H₂₆ClF₆N₆O 644.96 645 Rt: 11.27 (method O) 105  112

C₂₅H₂₄ClF₆N₅O 559.93 560 Rt: 10.48 (method O) 111  113

C₂₇H₂₅F₇N₆O 582.52 583 Rt: 10.82 (method O) 111  115

C₂₇H₂₉Cl₂F₄N₅O 586.45 586 Rt: 11.60 (method O) 114  118

C₂₆H₃₂ClN₅O 466.02 466 Rt: 6.10 (method P) 71 119

C₂₆H₃₂ClN₅O₂ 482.02 482 Rt: 4.79 (method P) 71 120

C₂₇H₃₄Cl₂N₆O 529.50 529 Rt: 3.82 (method P) 71 121

C₂₆H₃₁Cl₂N₅O₂ 516.46 516 Rt: 11.62 (method N) 71 122

C₂₈H₃₅Cl₂N₅O₂ 544.52 544 Rt: 12.50 (method N) 71 123

C₂₇H₃₄ClN₅O 480.04 480 Rt: 12.25 (method N) 71 124

C₂₆H₂₅Cl₂F₆N₅O 608.41 608 Rt: 14.02 (method N) 71 125

C₂₇H₃₁Cl₂F₃N₆O 583.48 583 Rt: 9.35 (method N) 71 126

C₂₆H₂₈Cl₂F₃N₅O₂ 570.43 570 Rt: 12.52 (method N) 71 127

C₂₄H₂₂ClF₃N₆O 502.92 503 Rt: 11.84 (method N) 71 128

C₂₃H₂₂Cl₂F₃N₅O₂ 528.35 528 Rt: 11.28 (method N) 71 129

C₂₄H₂₅Cl₂F₃N₆O 541.40 541 Rt: 8.90 (method N) 71 130

C₂₆H₂₃ClF₆N₆O 584.94 585 Rt: 13.92 (method N) 82 131

C₂₆H₂₇Cl₂F₃N₆O 567.433 567 Rt: 1.39 (method G) 82 132

C₂₄H₂₅ClF₃N₅O 491.94 492 Rt: 12.00 (method N) 9(f) 134

C₂₄H₂₅Cl₃F₃N₅O 562.85 562 Rt: 1.62 (method Q) 23 135

C₂₅H₂₇Cl₃F₃N₅O 576.88 576 Rt: 1.66 (method Q) 23 136

C₂₃H₂₁Cl₃F₅N₅O 584.8 584 Rt: 1.61 (method Q) 23 137

C₂₄H₂₄Cl₃F₄N₅O 580.84 580 Rt: 1.62 (method Q)) 23 138

C₂₅H₂₆Cl₃F₄N₅O 594.87 594 Rt: 1.65 (method Q) 23 139

C₂₅H₂₄Cl₃F₆N₅O 630.85 630 Rt: 1.69 (method Q) 23 140

C₂₆H₂₆Cl₃F₆N₅O 644.87 644 Rt: 1.72 (method Q) 23 141

C₂₄H₂₃Cl₃F₅N₅O 598.83 598 Rt: 1.64 (method Q) 23 142

C₂₄H₂₂Cl₃F₆N₅O 616.82 616 Rt: 1.65 (method Q) 23 143

C₂₅H₂₄Cl₃F₆N₅O 630.85 630 Rt: 1.68 (method Q) 23 144

C₂₇H₃₁Cl₃F₃N₅O 604.93 604 Rt: 1.73 (method Q) 23 145

C₂₆H₂₆Cl₃F₃N₆O 601.89 601 Rt: 1.63 (method Q) 23 146

C₂₄H₂₆Cl₃F₃N₆O 577.86 577 Rt: 1.40 (method Q) 23 147

C₂₅H₂₅Cl₃F₆N₆O 645.86 645 Rt: 1.57 (method Q) 23 148

C₂₄H₂₅Cl₃F₄N₆O 595.85 595 Rt: 1.41 (method Q) 23 149

C₂₆H₂₈Cl₃F₃N₆O 603.9 603 Rt: 1.42 (method Q) 23 150

C₂₆H₂₈Cl₃F₃N₆O 603.9 603 Rt: 1.42 (method Q) 23 151

C₂₅H₂₄Cl₃F₆N₅O₂ 646.84 646 Rt: 1.66 (method Q) 23 152

C₂₄H₂₂Cl₃F₆N₅O₂ 632.82 632 Rt: 1.63 (method Q) 23 153

C₂₆H₂₆Cl₃F₆N₅O₂ 660.87 660 Rt: 1.67 (method Q) 23 154

C₂₆H₂₆Cl₃F₆N₅O₂ 660.87 660 Rt: 1.68 (method Q) 23 155

C₂₅H₂₅Cl₃F₃N₅O 574.86 574 Rt: 1.64 (method Q) 23 156

C₂₆H₂₇Cl₃F₃N₅O 588.89 588 Rt: 1.68 (method Q) 23 157

C₂₅H₂₄Cl₃F₆N₅O 642.86 642 Rt: 1.70 (method Q) 23 158

C₂₅H₂₅Cl₃F₃N₅O₂ 590.86 590 Rt: 1.61 (method Q) 23 159

C₂₅H₂₆Cl₃F₃N₆O 589.87 589 Rt: 1.40 (method Q) 23 160

C₂₆H₂₆Cl₃F₄N₅O 606.88 606 Rt: 1.66 (method Q) 23 161

C₂₇H₂₈Cl₃F₄N₆O 615.91 615 Rt: 1.41 (method Q) 23 162

C₂₇H₂₈Cl₃F₃N₆O 615.91 615 Rt: 1.41 (method Q) 23 163

C₂₆H₂₇Cl₃F₄N₆O 621.89 621 Rt: 1.40 (method Q) 23 164

C₂₆H₂₆Cl₃F₅N₆O 639.88 639 Rt: 1.46 (method Q) 23 165

C₂₅H₂₆Cl₃F₃N₆O 589.87 589 Rt: 1.40 (method Q) 23 166

C₂₅H₂₆Cl₃F₃N₆O 589.87 589 Rt: 1.40 (method Q) 23 167

C₂₈H₂₄Cl₃F₄N₅O 628.88 628 Rt: 1.67 (method Q) 23 168

C₂₈H₂₃Cl₄F₄N₅O 663.33 662 Rt: 1.67 (method Q) 23 169

C₂₈H₂₄Cl₃F₄N₅O 628.88 628 Rt: 1.71 (method Q) 23 170

C₂₈H₂₃Cl₃F₅N₅O 646.87 646 Rt: 1.74 (method Q) 23 171

C₂₈H₂₄Cl₃F₄N₅O 628.88 628 Rt: 1.71 (method Q) 23 172

C₂₇H₂₄Cl₃F₃N₆O 611.88 611 Rt: 1.60 (method Q) 23 173

C₂₇H₂₃Cl₄F₃N₆O 646.33 645 Rt: 1.63 (method Q) 23 174

C₂₇H₂₃Cl₃F₄N₆O 629.87 629 Rt: 1.62 (method Q) 23 175

C₂₈H₂₆Cl₃F₃N₆O 625.91 625 Rt: 1.67 (method Q) 23 176

C₂₇H₂₄Cl₃F₃N₆O 611.88 611 Rt: 1.65 (method Q) 23 177

C₂₇H₂₃Cl₃F₄N₆O 629.87 629 Rt: 1.66 (method Q) 23 178

C₂₅H₂₂Cl₃F₃N₆OS 617.91 617 Rt: 1.64 (method Q) 23 179

C₂₆H₂₃Cl₄F₃N₆O 634.31 633 Rt: 1.69 (method Q) 23 180

C₂₅H₂₂Cl₄F₃N₇O 635.3 634 Rt: 1.66 (method Q) 23

The invention claimed is:
 1. A compound of formula (I)

in which R¹ represents halo, —OH, —CN, C₁₋₃ alkyl, C₂₋₆ alkynyl, or—OC₁₋₃ alkyl which latter three groups are optionally substituted by oneor more substituents selected from fluoro, —CN, ═O, —OH, —OCH₃, or—OCF₃; R², R³ and R⁴ independently represent hydrogen, halo, —CN, C₁₋₃alkyl, or —OC₁₋₃ alkyl which latter two alkyl groups are optionallysubstituted by one or more substituents selected from fluoro, —CN, ═O,—OH, —OCH₃, or —OCF₃; R^(a) and R^(b) independently represent hydrogen,or C₁₋₃ alkyl which is optionally substituted by one or more fluorineatoms, or both together with the carbon atom which they are bound to,form a C₃₋₇ cycloalkyl ring, or a 4-6 membered heterocycloalkyl ringwhich latter two groups are optionally substituted by one or morefluorine atoms; W represents —C(O)—, —S(O)—, —S(O)₂—, —C(O)O—, or—C(O)NR^(d)— which groups are bound to the nitrogen of the —NH— moietyvia carbon or sulfur atom; R^(d) represents hydrogen, or C₁₋₃ alkyl; Mrepresents C₁₋₈ alkyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl-C₀₋₄ alkyl-, or4-10 membered heterocycloalkyl-C₀₋₄ alkyl- which latter four groups areoptionally substituted by one or more groups selected from fluoro, —OH,═O, —CN, —NH₂, C₁₋₃ alkyl, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, azetidinyl,pyrrolidinyl, piperidinyl, —OC₁₋₃ alkyl, [which latter seven alkylgroups can be substituted by one or more substituents selected fromfluoro, —OH, —CN, —OC₁₋₂ alkyl (which latter alkyl group is optionallysubstituted by one or more fluorine atoms)], aryl, or heteroaryl [whichlatter two groups are optionally substituted by one or more substituentsselected from halo, —OH, —CN, C₁₋₃ alkyl, —OC₁₋₃ alkyl (which latter twoalkyl groups are optionally substituted by one or more fluorine atoms)],or aryl, or heteroaryl which latter two groups are optionallysubstituted by one or more substituents selected from halo, —OH, —CN,—NH₂, aryl, heteroaryl [which latter two groups are optionallysubstituted by one or more substituents selected from halo, —OH, —CN,C₁₋₃ alkyl, —OC₁₋₃ alkyl (which latter two alkyl groups are optionallysubstituted by one or more fluorine atoms)], C₁₋₇alkyl, C₂₋₇ alkynyl,C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, —NH₂, —NH(C₁₋₃ alkyl),—N(C₁₋₃ alkyl)₂, —OC₁₋₃ alkyl, —O—C₀₋₂alkyl-aryl, or —SC₁₋₃ alkyl,(which latter alkyl, alkynyl, heterocycloalkyl, aryl or cycloalkylgroups are optionally substituted by one or more substituents selectedfrom fluoro, —CN, ═O, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —OH, or—OC₁₋₃alkyl)]; R⁶ represents hydrogen, C₁₋₅ alkyl, C₃₋₆ alkynyl, 4-7membered hetero-cycloalkyl-C₀₋₂alkyl or C₃₋₇cycloalkyl-C₀₋₂alkyl (whichlatter four groups are optionally substituted by one or moresubstituents selected from fluoro, —CN, ═O, C₁₋₃ alkyl, —OH, —NH₂,—OC₁₋₃ alkyl, —NH(C₁₋₃ alkyl), or —N(C₁₋₃ alkyl)₂); R⁷, R⁸ and R⁹independently represent hydrogen, halo, —CN, C₁₋₅ alkyl, C₃₋₅cycloalkyl-C₀₋₂alkyl-, C₁₋₅ alkyl-O—, or C₃₋₅cycloalkyl-C₀₋₂alkyl-O— (inwhich latter four groups the alkyl and cycloalkyl fragments areoptionally substituted by one or more substituents selected from fluoro,—CN, —OH, —OC₁₋₃ alkyl or by one or more C₁₋₃ alkyl groups which areoptionally substituted by one or more fluorine atoms); A represents—NHR¹⁰, —NR¹⁰R¹¹, or a 4-10-membered heterocycloalkyl group which isbound to the benzimidazole through a nitrogen atom, and which isoptionally substituted by one or more substituents R¹²; R¹⁰ and R¹¹independently represent C₁₋₇ alkyl, C₃₋₇ cycloalkyl-C₀₋₄ alkyl- or C₄₋₇heterocycloalkyl-C₀₋₄ alkyl- [which latter three groups are optionallysubstituted by one or more groups selected from fluoro, —OH, NH₂, —CN,C₁₋₃ alkyl, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —OC₁₋₅ alkyl, —OC₃₋₆cycloalkyl, or —OC₄₋₆ heterocycloalkyl (which latter six groups areoptionally substituted by one or more substituents selected from fluoro,—CF₃, —CHF₂, —CH₂F, or —CH₃)], or aryl-C₀₋₄ alkyl-, or heteroaryl-C₀₋₄alkyl-[which latter two groups are optionally substituted by one or moresubstituents selected from halo, —OH, —CN, C₁₋₃ alkyl, C₃₋₅ cycloalkyl,C₁₋₃ alkyl-O—, or C₃₋₅ cycloalkyl-O— (which latter four groups areoptionally substituted by one or more fluorine atoms)]; each R¹²independently represents halo, —OH, —NH₂, ═O, —CN, C₁₋₄ alkyl, C₃₋₅cycloalkyl-C₀₋₂ alkyl-, C₄₋₅ heterocycloalkyl-C₀₋₂ alkyl-, C₁₋₄alkyl-O—, C₁₋₃ alkyl-C(═O)—, —C(═O)—NH(C₁₋₃ alkyl), or —C(═O)—N(C₁₋₃alkyl)₂ [which latter six groups are optionally substituted by one ormore groups selected from fluoro, —OH, oxo, —NH₂, —CN, C₁₋₃ alkyl,—NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —OC₁₋₃ alkyl, or —OC₃₋₅ cycloalkyl[which latter five groups are optionally substituted by one or moresubstituents selected from fluoro, —CF₃, —CHF₂, or —CH₂F], or aryl-C₀₋₄alkyl-, or heteroaryl-C₀₋₄ alkyl-[which latter two groups are optionallysubstituted by one or more substituents selected from halo, —OH, —CN,C₁₋₃ alkyl, C₃₋₅ cycloalkyl, C₁₋₃ alkyl-O—, or C₃₋₅ cycloalkyl-O— (whichlatter four groups are optionally substituted by one or more fluorineatoms)]; or a salt thereof.
 2. A compound according to claim 1, whereinR¹ represents halo, C₁₋₃ alkyl, or —OC₁₋₃ alkyl which latter two groupsare optionally substituted by one or more fluorine atoms; or apharmaceutically acceptable salt thereof.
 3. A compound according toclaim 1, wherein R³ and R⁴ independently represent hydrogen, or halo; ora pharmaceutically acceptable salt thereof.
 4. A compound according toclaim 1, wherein M represents C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl-C₀₋₁ alkyl-, oxetanyl-, tetrahydrofuranyl-, azetidinyl-,pyrrolidinyl-, or piperidinyl- or one of the following heterocyclicgroups

all of which groups are optionally substituted by one or more groupsselected from fluoro, —OH, —CN, —NH₂, C₁₋₃ alkyl, —NH(C₁₋₂ alkyl),—N(C₁₋₂ alkyl)₂, or —OC₁₋₂ alkyl [which latter four alkyl groups areoptionally substituted by one or more substituents selected fromfluoro], phenyl, or imidazolyl-[which latter two groups are optionallysubstituted by one or more substituents selected from halo, C₁₋₂ alkyl,or OC₁₋₂alkyl (which latter two alkyl groups are optionally substitutedby one or more fluorine atoms)], or phenyl, naphthyl, furanyl, thienyl,oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, pyrazolyl, pyridinyl,pyrazinyl, or quinolynyl which latter twelve groups are optionallysubstituted by one or more substituents selected from halo, aryl,heteroaryl [which latter two groups are optionally substituted by one ormore substituents selected from halo, —CH₃, —CH₂F, —CHF₂, or —CF₃], C₁₋₂alkyl, —OC₁₋₂ alkyl [which latter two groups are optionally substitutedby one or more fluorine atoms], C₂₋₃ alkynyl, or —O—C₀₋₂alkyl-phenyl [inwhich latter group the phenyl is optionally substituted by one or moresubstituents selected from halo, —CH₃, —CH₂F, —CHF₂, or —CF₃]; or apharmaceutically acceptable salt thereof.
 5. A compound according toclaim 1, wherein R⁷ and R⁹ independently represent hydrogen, halo, —CN,or C₁₋₃ alkyl optionally substituted by one or more fluorine atoms; or apharmaceutically acceptable salt thereof.
 6. A compound according toclaim 1, wherein A represents —NHR¹⁰, —NR¹⁰R¹¹, or azetidinyl-,pyrrolidinyl-, piperidinyl-, morpholinyl-, piperazinyl- or

all of which heterocyclic groups are optionally substituted by one ormore substituents R¹² and annulated to a phenyl or a 5- or 6-memberedheteroaryl ring, while the above mentioned groups are bonded to thebenzimidazole core through a nitrogen atom; R¹⁰ and R¹¹ independentlyrepresent C₁₋₅ alkyl, or C₃₋₆ cycloalkyl-C₀₋₁ alkyl-[which latter twogroups are optionally substituted by one or more groups selected fromfluoro, —OH, or C₁₋₃ alkyl], or aryl-C₀₋₁ alkyl- optionally substitutedby one or more substituents selected from halo, —OH, —CN, C₁₋₃ alkyl, orC₁₋₃ alkyl-O—[which latter two groups are optionally substituted by oneor more fluorine atoms]; each R¹² independently represents halo, —OH,—CN, C₁₋₄ alkyl, C₁₋₂ alkyl-O—, C₁₋₂ alkyl-C(═O)—, —C(═O)—NH(C₁₋₂alkyl), or —C(═O)—N(C₁₋₂ alkyl)₂ [which latter five groups areoptionally substituted by one or more groups selected from fluoro, —OH,C₁₋₃ alkyl, —NH(C₁₋₂ alkyl), —N(C₁₋₂ alkyl)₂, or —OC₁₋₂ alkyl (whichlatter four groups are optionally substituted by one or moresubstituents selected from fluoro, CF₃, CHF₂ or CH₂F)], or phenyloptionally substituted by one or more substituents selected from halo orC₁₋₃ alkyl which is optionally substituted by one or more fluorineatoms; or a pharmaceutically acceptable salt thereof.
 7. A compoundaccording to claim 1, namely a compound of formula Ia

in which R¹ represents halo, C₁₋₃ alkyl, or —OC₁₋₃ alkyl which lattertwo groups are optionally substituted by one or more fluorine atoms; R²represents hydrogen, halo, or C₁₋₃ alkyl optionally substituted by oneor more fluorine atoms; R³ and R⁴ independently represent hydrogen, orhalo; W represents —C(O)—, —S(O)₂—, or —C(O)O— which groups are bound tothe nitrogen of the —NH— moiety via carbon or sulfur atom; M representsC₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl-C₀₋₁ alkyl-, oxetanyl-,tetrahydrofuranyl-, azetidinyl-, pyrrolidinyl-, or piperidinyl- or oneof the following heterocyclic groups

all of which groups are optionally substituted by one or more groupsselected from fluoro, —OH, —CN, —NH₂, C₁₋₃ alkyl, —NH(C₁₋₂ alkyl),—N(C₁₋₂ alkyl)₂, or —OC₁₋₂ alkyl, [which latter four alkyl groups areoptionally substituted by one or more fluorine atoms], phenyl,imidazolyl-[which latter two groups are optionally substituted by one ormore substituents selected from halo, C₁₋₂ alkyl, or OC₁₋₂alkyl (whichlatter two alkyl groups are optionally substituted by one or morefluorine atoms)], or phenyl, naphthyl, furanyl, thienyl, oxazolyl,isoxazolyl, thiazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, orquinolynyl which latter twelve groups are optionally substituted by oneor more substituents selected from halo, aryl, heteroaryl [which lattertwo groups are optionally substituted by one or more substituentsselected from halo, —CH₃, —CH₂F, —CHF₂, —CF₃], C₁₋₂ alkyl, —OC₁₋₂ alkyl[which latter two groups are optionally substituted by one or morefluorine atoms], C₂₋₃ alkynyl, or —O—C₀₋₂alkyl-phenyl [in which lattergroup the phenyl is optionally substituted by one or more substituentsselected from halo, —CH₃, —CH₂F, —CHF₂, or —CF₃]; R⁶ representshydrogen, C₁₋₅ alkyl or C₃₋₇cycloalkyl-C₀₋₂alkyl [which latter twogroups are optionally substituted by one or more substituents selectedfrom fluoro, C₁₋₃ alkyl, —OC₁₋₃ alkyl, —NH(C₁₋₃ alkyl), or —N(C₁₋₃alkyl)₂]; R⁸ represents hydrogen, halo, —CN, C₁₋₅ alkyl, or C₃₋₅cycloalkyl-C₀₋₂ alkyl-(in which latter two groups the alkyl andcycloalkyl fragments are optionally substituted by one or more fluorineatoms, or by one or more C₁₋₃ alkyl groups which are optionallysubstituted by one or more fluorine atoms) R⁹ represents hydrogen, halo,—CN, or C₁₋₃ alkyl optionally substituted by one or more substituentsselected from fluorine atoms; A represents —NHR¹⁰, —NR¹⁰R¹¹, orazetidinyl-, pyrrolidinyl-, piperidinyl-, morpholinyl-, piperazinyl- or

all of which heterocyclic groups can optionally be substituted by one ormore substituents R¹² and optionally annulated to a phenyl or a 5- or6-membered heteroaryl ring, whereby the above mentioned groups arebonded to the benzimidazole core through a nitrogen atom; R¹⁰ and R¹¹independently represent C₁₋₅ alkyl or C₃₋₆ cycloalkyl-C₀₋₁ alkyl-[whichlatter two groups are optionally substituted by one or more groupsselected from: fluoro, —OH, C₁₋₃ alkyl], or aryl-C₀₋₁ alkyl- which canbe substituted by one or more substituents selected from halo, —OH, —CN,C₁₋₃ alkyl, or C₁₋₃ alkyl-O—[which latter two groups are optionallysubstituted by one or more fluorine atoms]; each R¹² independentlyrepresents halo, —OH, —CN, C₁₋₄ alkyl, C₁₋₂ alkyl-O—, C₁₋₂ alkyl-C(═O)—,—C(═O)—NH(C₁₋₂ alkyl), or —C(═O)—N(C₁₋₂ alkyl)₂ [which latter fivegroups are optionally substituted by one or more groups selected fromfluoro, —OH, C₁₋₃ alkyl, —NH(C₁₋₂ alkyl), —N(C₁₋₂ alkyl)₂, or —OC₁₋₂alkyl, (which latter four groups are optionally substituted by one ormore substituents selected from fluoro, CF₃, CHF₂ or CH₂F)], or phenyloptionally substituted by one or more substituents selected from halo orC₁₋₃ alkyl which is optionally substituted by one or more fluorineatoms; or a pharmaceutically acceptable salt thereof.
 8. A compoundaccording to claim 1, wherein R⁸ represents hydrogen, fluoro, chloro,CF₃, or —CN; or a pharmaceutically acceptable salt thereof.
 9. Acompound according to claim 1, wherein A represents a group selectedfrom

or a pharmaceutically acceptable salt thereof.
 10. A compound accordingto claim 1, wherein M represents a group selected from

or a pharmaceutically acceptable salt thereof.
 11. A compound accordingto claim 1, namely a compound of formula (Ia)

in which R¹ represents fluoro, chloro, CH₃, CHF₂, CH₂F, CF₃ or —OCF₃; R²represents hydrogen, fluoro or chloro; R³ and R⁴ independently representhydrogen, or fluoro; R⁶ represents hydrogen, —CH₃, —CH₂CF₃,cyclopropylmethyl-, —CH₂CH₂—O—CH₃, or —CH₂CH₂—N(CH₃)₂; R⁸ representshydrogen, fluoro, chloro, CF₃, or —CN; R⁹ represents hydrogen, orfluoro; A represents a group selected from

W represents —C(O)—, or —S(O)₂— which groups are bound to the nitrogenof the —NH— moiety via carbon or sulfur atom; M represents a groupselected from

or a pharmaceutically acceptable salt thereof.
 12. A compound accordingto claim 1 selected from the compounds below: Structure 1

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and pharmaceutically acceptable salts thereof.
 13. A pharmaceuticalcomposition comprising at least one compound according to claim 1, or apharmaceutically acceptable salt thereof, in a mixture with apharmaceutically acceptable adjuvant, diluent and/or carrier.
 14. Amethod for the treatment or prevention of an inflammatory disease in apatient comprising administering to said patient a therapeuticallyeffective amount of a compound according to claim 1, or apharmaceutically acceptable salt thereof.